TW200404052A

TW200404052A - Hydroxy tetrahydro-naphthalenylurea derivatives

Info

Publication number: TW200404052A
Application number: TW092112380A
Authority: TW
Inventors: Takeshi Yura; Muneto Mogi; Klaus Urbahns; Hiroshi Fujishima; Tsutomu Masuda; Moriwaki Toshiya; Yoshida Nagahiro; Kokubo Toshio; Shiroo Masahiro; Tajimi Masaomi; Tsukimi Yasuhiro; Yamamoto Noriyuki
Original assignee: Bayer Ag
Priority date: 2002-05-08
Filing date: 2003-05-07
Publication date: 2004-03-16
Also published as: BR0309940A; DK1506167T3; CN1307150C; US7612113B2; HRP20041167A2; CN1665778A; JP4335131B2; WO2003095420A1; JP2005524717A; AU2003229734A1; PL210288B1; IL165004A; AU2003229734B2; MXPA04010938A; CA2487238C; PL373257A1; DE60315973D1; EP1506167B1; ES2292959T3; NO20045359L

Abstract

This invention relates to tetrahydro-naphthalene derivatives and salts thereof which is useful as an active ingredient of pharmaceutical preparations. The tetrahydro-naphthalene derivatives of the present invention have an excellent activity as VR1 antagonist and useful for the prophylaxis and treatment of diseases associated with VR1 activity, in particular for the treatment of urge urinary incontinence, overactive bladder, chronic pain, neuropathic pain, postoperative pain, rheumatoid arthritic pain, neuralgia, neuropathies, algesia, nerve injury, ischaemia, neurodegeneration, stroke, incontinence, inflammatory disorders such as asthma and COPD.

Description

200404052 A7 五、發明說明 B7 10 15 經濟部智慧財產局員工消費合作社印製 20 斤。本發明係有關適用為醫藥製劑之活性成分之羥基_四氫:脲衍生物。本發明之羥基-四氫-萘脲衍生物具有類香草又體(VR)擷4几活性，可用於預防及治療與活性有關之疾病，特疋言之用於治療尿急性尿失禁、過度活性膀，二忮性疼痛、神經病變性疼痛、手術後疼痛、類風濕關砟久疼痛、神經痛、神經病變、痛覺、神經受傷、絕血、神經變性、中風、失禁與/或發炎疾病如：氣喘及慢性阻塞性肺病（COPD)。、尿失禁（UI)為不自主地流出尿液。尿急性尿失禁（UUI〕為最《見之一種XJI，同時會出現經常因尿道關閉機制缺陷造成之壓力尿失禁（SUTVUUI經常與導致神經元傷害之神經病變或疾病有關，如：癡呆症、巴金森氏症、多發 11硬化、中風與糖尿病，但其亦發生在沒有此等病變之個體身上。其中一種常見之UUI肇因為過度活性膀胱 (〇AB) ’其係一種涉及迫肌收縮異常及不穩定性所造成頻尿及尿急症狀之醫學病症。目刖市面上有數種治療尿失禁之藥物，主要用於協助二療UUI。OAB之療法著重於會影響周邊神經控制機制之藥物或彼等直接作用在膀胱迫肌平滑肌收縮上之藥物，主要重點在於發展抗膽鹼激導性劑。此等藥劑可抑制控制膀胱排空之副父感神經或可對膀胱之迫肌直接產生解痙攣效用。結果降低膀胱内壓力，提高膀胱容量及降低膀胱收縮頻率。口服用活性抗膽鹼激導性劑（如：丙胺太林 200404052 A7 B7 五、發明說明（2) (propantheline (ProBanthine))、甲苯若定酒石酸鹽 (tolterodine tartrate (Detrol))與氧丁基寧（〇xybutynin (Ditropan))為最常處方之藥物。然而，其最大缺點在於無法接受之副作用，如：口乾、視覺異常、便秘與中樞神經 5 系統障礙。此等副作用導致適應性差。單就口乾一項症狀即令70%患者抱怨氧丁基寧之不適應性。目前療法之不適應性突顯對副作用較少之新穎、有效 '安全之口服藥物之需求。 10 先前技術類香草化合物之特徵在於具有香草基或同等官能基。類香草化合物或類香草受體調節劑之數項實例為香草(4_經基-3-曱氧基-苯曱醛）、癒創木酚（2-甲氧基_苯酚）、薑油酮（4-/4-羥基-3-甲氧苯基/-2-丁酮）、丁子香酚_ (2-甲氧基_ 15 /2-丙烯基/苯紛）、與辣椒素（8·甲基-N_香草基-6-壬烯·醯胺）。經濟部智慧財產局員工消費合作社印製其中辣椒素為”辣”椒中之主要辛辣成分，為C-纖維傳入神經元去敏化之專一性神經毒素。辣椒素會與主要表現在側根神經節(DRG)或包括Ο纖維神經末端之傳入感覺纖 2〇維神經末端之細胞體中之類香草受體（VR1)交互作用 [Tominaga M，Caterina MJ，Malmberg AB，Rosen TA，Gilbert H，Skinner K，Raumann BE，Basbaum AI，Julius D: The cloned capsaicin receptor integrates multiple pain-producing stimuli· Neuron. 21: 531-543, 1998]。最近已選殖出 VR1 受 -4- 本紙張尺度適用中國國家標準(CNS)A4規格（210x297公釐） 200404052 A7 B7 五、發明說明（3 ) 體[Caterina MJ，Schumacher MA; Tominaga M，Rosen TA， Levine JD，Julius D: Nature 389: 816-824，（1997)]，經判斷為具有6個結構上與TRP(過渡受體電位）通道族群相關之穿膜功能部位之非選擇性陽離子通道。辣椒素與VR1之 5 結合可以使納、詞及可能使舒離子濃度梯度下降，引起初期去極化及自神經末端釋出神經遞質。因此，VR1可視為在病症或疾病中誘發神經元訊號之化學與物理性刺激之分子整合物。經濟部智慧財產局員工消費合作社印製許多直接或間接證據顯示VR1活性與如：疼痛、絕 10 血及發炎等疾病之相關性（例如：WO 99/00115與 00/50387)。此外，並已證實，VR1轉導之反射訊號涉及脊髓反射途徑受損或異常之患者之過度活性膀胱[De Groat WC: A neurologic basis for the overactive bladder. Urology 50 (6A Suppl): 36-52, 1997]。使用 VR1 促效劑(如：辣椒 15 素）消耗神經遞質，使傳入神經去敏化之結果在治療與脊柱受傷及多發性硬化有關之膀胱功能障礙上有很好成效 [(MaggiCA: Therapeutic potential ofcapsacin-like molecules -Studies in animals and humans. Life Sciences 51: 1777-1781, 1992)與（DeRidder D; Chandiramani V;· Dasgupta P; 20 VanPoppel H; Baert L; Fowler CJ: Intravesical capsaicin as a treatment for refractory detrusor hyperreflexia: A dual center study with long-term followup. J.Urol. 158: 2087-2092,1997)]。可預期VR1受體之擷抗性應可阻斷神經遞質釋出，本紙張尺度適用中國國家標準(CNS)A4規格（210x297公釐） 200404052 A7 B7 五、發明說明（4 ) 結果可預防及治療與VR1活性有社病症與疾病。因此，VIU受體之操抗劑應可用於預防及治療包括：慢性疼痛、神經病變性疼痛、手術後疼痛、類風濕關節炎疼痛、神經痛、神經病變、痛覺、神經受傷、触、神經變性、中風、失禁、發炎疾病如：氣喘及COPD、尿 ⑽如：尿急性尿失禁(UUI)，與/或過度活性膀胱。-WO 00/50387揭示具有類香草促效劑活性之表之化合物：200404052 A7 V. Description of the invention B7 10 15 20 kg was printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs. The present invention relates to a hydroxy-tetrahydro: urea derivative suitable as an active ingredient of a pharmaceutical preparation. The hydroxy-tetrahydro-naphthyl urea derivative of the present invention has vanilloid-like (VR) activity and can be used for the prevention and treatment of diseases related to the activity, in particular for the treatment of acute urinary incontinence and excessive activity Bladder pain, diabetic pain, neuropathic pain, postoperative pain, rheumatoid pain, neuralgia, neuropathy, pain, nerve injury, hemostasis, neurodegeneration, stroke, incontinence and / or inflammatory diseases such as asthma and chronic Obstructive pulmonary disease (COPD). 2. Urinary incontinence (UI) is the involuntary outflow of urine. Urinary acute urinary incontinence (UUI) is the most commonly seen type of XJI, and stress urinary incontinence often caused by defects in the urethral closure mechanism (SUTVUUI is often associated with neuropathy or diseases that cause neuronal damage, such as dementia, barkin Sen's disease, multiple sclerosis, stroke, and diabetes, but it also occurs in individuals without these lesions. One of the common UUI is caused by the overactive bladder (〇AB) 'It is a type of abnormal muscle contraction involving The medical condition of frequent urinary and urgency symptoms caused by stability. There are several drugs on the market for the treatment of urinary incontinence, which are mainly used to assist the second treatment of UUI. The treatment of OAB focuses on drugs or other drugs that affect peripheral nerve control mechanisms. Drugs that directly act on the contraction of bladder muscle smooth muscle, the main focus is on the development of anticholinergic agents. These agents can inhibit the parasensory nerve that controls bladder emptying or can directly produce antispasmodic effects on the bladder muscles .Results Reduce the pressure in the bladder, increase the bladder capacity and reduce the frequency of bladder contraction. Oral active anticholinergic agents (such as: propylamine Tailin 200404052 A7 B7 V. Description of the Invention (2) (propantheline (ProBanthine)), tolterodine tartrate (Detrol) and oxybutynin (Dixypan) are the most commonly prescribed drugs. However, its biggest disadvantage is the unacceptable side effects, such as: dry mouth, visual abnormalities, constipation, and central nervous system 5 disorders. These side effects lead to poor adaptability. A symptom of dry mouth alone makes 70% of patients complain of oxybutynin Inadaptability. The inadequacy of current therapies highlights the need for novel, effective, and safe oral medications with fewer side effects. 10 Prior art vanilla compounds are characterized by having vanillyl or equivalent functional groups. Vanilla-like compounds or similar Some examples of vanilla receptor modulators are vanilla (4-Cyclo-3-methoxy-phenylbenzoaldehyde), guaiacol (2-methoxy_phenol), zingerone (4- / 4 -Hydroxy-3-methoxyphenyl / -2-butanone), eugenol_ (2-methoxy_ 15 / 2-propenyl / benzophenone), and capsaicin (8 · methyl-N_ Vanillyl-6-nonene · amidamine). Consumer Cooperatives, Intellectual Property Bureau, Ministry of Economic Affairs Printed in which capsaicin is the main spicy component of "spicy" pepper, and is a specific neurotoxin that desensitizes C-fiber afferent neurons. Capsaicin is mainly expressed in lateral root ganglia (DRG) or includes 0 Afferent sensory fibers at the nerve ending Interactions with vanilla receptors (VR1) in the cell body of the 20-dimensional nerve terminal [Tominaga M, Caterina MJ, Malmberg AB, Rosen TA, Gilbert H, Skinner K, Raumann BE, Basbaum AI , Julius D: The cloned capsaicin receptor integrates multiple pain-producing stimuli · Neuron. 21: 531-543, 1998]. Recently, VR1 has been selected. The paper size is applicable to the Chinese National Standard (CNS) A4 specification (210x297 mm) 200404052 A7 B7 V. Description of invention (3) Body [Caterina MJ, Schumacher MA; Tominaga M, Rosen TA , Levine JD, Julius D: Nature 389: 816-824, (1997)], was judged to have six non-selective cation channels that are structurally related to TRP (transition receptor potential) channel family through-membrane functional sites. The combination of capsaicin and VR1-5 can reduce the concentration of sodium, ions, and possibly reduce the concentration of Shu ion, causing initial depolarization and release of neurotransmitters from nerve endings. Therefore, VR1 can be regarded as a molecular integrative of chemical and physical stimuli that induce neuron signals in a disorder or disease. Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs Many direct or indirect evidences show the correlation between VR1 activity and diseases such as pain, absolute blood, and inflammation (eg, WO 99/00115 and 00/50387). In addition, it has been confirmed that the reflex signal transduced by VR1 involves an overactive bladder in patients with impaired or abnormal spinal cord reflex pathways [De Groat WC: A neurologic basis for the overactive bladder. Urology 50 (6A Suppl): 36-52, 1997]. The use of VR1 agonists (such as capsaicin 15) consumes neurotransmitters and desensitizes the afferent nerves. It is very effective in treating bladder dysfunction associated with spinal injuries and multiple sclerosis [(MaggiCA: Therapeutic potential ofcapsacin-like molecules -Studies in animals and humans. Life Sciences 51: 1777-1781, 1992) and (DeRidder D; Chandiramani V; · Dasgupta P; 20 VanPoppel H; Baert L; Fowler CJ: Intravesical capsaicin as a treatment for refractory detrusor hyperreflexia: A dual center study with long-term followup. J. Urol. 158: 2087-2092, 1997)]. It is expected that the VR1 receptor's capture resistance should be able to block the release of neurotransmitters. This paper size applies the Chinese National Standard (CNS) A4 specification (210x297 mm) 200404052 A7 B7 V. Description of the invention (4) The results can be prevented and Treatment and VR1 activity have social disorders and diseases. Therefore, VIU receptor antagonists should be available for prevention and treatment including: chronic pain, neuropathic pain, postoperative pain, rheumatoid arthritis pain, neuralgia, neuropathy, pain, nerve injury, touch, neurodegeneration, Stroke, incontinence, inflammatory diseases such as asthma and COPD, urinary dysfunction such as acute urinary incontinence (UUI), and / or overactive bladder. -WO 00/50387 discloses compounds of the table having vanilla-like agonist activity:

10 其中； xp為氧或硫原子；經濟部智慧財產局員工消費合作社印製10 of which; xp is an oxygen or sulfur atom; printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs

Ap 為-NHCH2-或 _Cti2-; 20 Ra為經取代或未取代之Ci 4烷基，或Ralc〇 · 其中，Ap is -NHCH2- or _Cti2-; 20 Ra is substituted or unsubstituted Ci 4 alkyl, or Ralc. Where,

Ral =具有ι·18個碳料之錄、2、18個碳基、或6-10個碳原子之經取代或未取/二烯 Rb為氫原子、1-6個碳原子之烧基、η個石炭原元 -6- 本纸張尺度適用中國國家標準公 200404052 A7 B7 五、發明說明（5 ) 基、1-6個碳原子之鹵烷基或_原子；Ral = 1 or 18 carbons, 2 or 18 carbons, or substituted or unselected / diene Rb is a hydrogen atom, 1 to 6 carbons, η carbon original element-6- This paper size applies to Chinese National Standard 200404052 A7 B7 V. Description of the invention (5) group, haloalkyl or _ atom of 1-6 carbon atoms;

Rc為氫原子、1-4個碳原子之烷基、胺基烷基、二酸單酉旨或α -烧基酸；且星號*代表對掌性碳原子， 5 及其醫藥上可接受之鹽。 WO 2000/61581揭示如下通式代表之胺衍生物：經濟部智慧財產局員工消費合作社印製Rc is a hydrogen atom, an alkyl group of 1 to 4 carbon atoms, an aminoalkyl group, a diacid or α-alkylene; and an asterisk * represents a palmar carbon atom, 5 and its pharmaceutically acceptable salt. WO 2000/61581 discloses amine derivatives represented by the following formula: Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs

20 劑其中 (Rf，R”)代表(F，F)、（CF3，H)、或(iPr，iPr〇其適用為糖尿病、高血脂、動脈粥瘤硬化與癌症之藥 WO 00/75106揭示如下式代表之化合物： -7- 三：:本紙張尺度適用中國國家標準(CNS)A4規格（210 X 297公爱) 200404052 A7 B7 五、發明說明（6 )20 doses where (Rf, R ") represents (F, F), (CF3, H), or (iPr, iPr0) which is suitable for diabetes, hyperlipidemia, atherosclerosis and cancer medicine WO 00/75106 is disclosed below Compounds represented by the formula: -7- 3: This paper size applies the Chinese National Standard (CNS) A4 specification (210 X 297 public love) 200404052 A7 B7 V. Description of the invention (6)

10 其中 z代表 15 又 H2N 、(CH2) 1— 9010 where z represents 15 and H2N, (CH2) 1-90

HN 丨’ 、(CH2) 或 OH R. 91/ 〇經濟部智慧財產局員工消費合作社印製 20 其中 R9G為氫、CM2烷基、C3_8環烷基，等等，且R91 為胺基-Ci_6烧基、胺魏基_Ci_6烧基、或經胺基-被基Ci_6烧基，且 R9G與R91分別獨立選自下列各物組成之群中：本紙張尺度適用中國國家標準(CNS)A4規格（210x297公釐） 200404052 A7 B7 五、發明說明（7) H、Ci_6烷基、Cw烷硫基、Cm烷氧基氯、溴、峨與硝基；其適用於治療哺乳動物中MMP-所媒介之疾病。 WO 00/55152揭示如下通式代表之化合物：HN 丨 ', (CH2) or OH R. 91 / 〇 Printed by the Intellectual Property Bureau of the Ministry of Economic Affairs and Consumer Cooperatives 20 where R9G is hydrogen, CM2 alkyl, C3_8 cycloalkyl, etc., and R91 is amine-Ci_6 Group, amine group, Ci_6 alkyl group, or amine group-Ci-6 alkyl group, and R9G and R91 are independently selected from the group consisting of the following: This paper size applies to China National Standard (CNS) A4 specifications ( (210x297 mm) 200404052 A7 B7 V. Description of the invention (7) H, Ci_6 alkyl, Cw alkylthio, Cm alkoxy chloride, bromine, fluorene and nitro; it is suitable for treating MMP in mammals disease. WO 00/55152 discloses compounds represented by the following formula:

XX

Ar,Ar,

/A「fL—Q 、ίί 經濟部智慧財產局員工消費合作、社印製其中 10 Αι^為雜環； Αι*2為四氯茶基；及 L與Q如本說明書中之定義；其適用為治療發炎、免疫相關疾病、疼痛與糖尿病^ 藥劑。 15 然而，此等參考文獻均未揭示具有VR1擷抗活性之$ 純羥基-四氫-萘脲衍生物。現在需要發展一種具有有效VR1擷抗活性且可用於予防及治療與VR1活性有關之疾病，特定言之尿失禁、石急性尿失禁、過度活性膀胱及疼痛，與/或炎症如··氣$ 20 與COPD之化合物。發明内容本發明提出一種式(I)羥基_四氫萘脲衍生物、其互變異構型與立體異構型，及其鹽：/ A 「fL—Q, ίί The consumer property cooperation of the Intellectual Property Bureau of the Ministry of Economic Affairs, which is printed by the company, where 10 Αι ^ is a heterocyclic ring; Αι * 2 is a tetrachloro tea group; and L and Q are as defined in this specification; it applies Agents for the treatment of inflammation, immune-related diseases, pain, and diabetes ^ 15 However, none of these references have disclosed a pure hydroxy-tetrahydro-naphthyl urea derivative with VR1 capture activity. Now it is necessary to develop a VR1 capture with effective It is anti-active and can be used to prevent and treat diseases related to VR1 activity, specifically urinary incontinence, acute urinary incontinence, overactive bladder and pain, and / or inflammation such as qi $ 20 and COPD compounds. SUMMARY OF THE INVENTION The invention proposes a hydroxy-tetralone urea derivative of formula (I), its tautomeric and stereoisomeric forms, and salts thereof:

200404052 A7 B7 五、發明說明（8 ) 〇人200404052 A7 B7 V. Description of Invention (8) 〇

.X.X

HNHN

(I) 其中 X代表Cw烷基 10(I) where X represents Cw alkyl 10

•R3• R3

或 15 其中 Y代表一直接鍵結 R R7 經濟部智慧財產局員工消費合作社印製Or 15 of which Y represents a direct bond R R7 printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs

R 或 20 R4 R1 R1、R2與R3分別獨立代表氫、鹵素、羥基、硝基、魏基、胺基、Ci_6烧胺基、二(Ci_6 烷基）胺基、c3_8環烷胺基、Cw烷氧羰 -10- 本紙張尺度適用中國國家標準(CNS)A4規格（210x297公釐） 200404052 A7 B7 五、發明說明（9 ) 10 15 基、苯基、苯甲基、續基、Cm烷醯胺基、胺甲醯基、K6烷醯甲醯基、氰基、可視需要^氰Cl_6烷胺烷氧幾基或單-、二-或烷基、可視需要經單-、二_咬_之Cl-6 代之Cl-6烧氧基、可視需要素取烧基取代之苯氧基、或可相 C!·6 J現需要經單，一-或二_素取代之Cl_6境硬基.R4、R5、R6、與R7分別獨立代表或苯基； Ά燒基 Z1代表氫或Cw烷基；及 Z2代表氩、齒素或Cw烷基。式(I)羥基-四氫·萘脲衍生物、其互變異構型與立體異構型、及其鹽展現優越之VR1擷抗活性。因此，其特別適用於預防及治療與VR1活性有關之疾病，特定言之用於治療尿急性尿失禁與/或過度活性膀胱。較佳者’式(I)羥基_四氫-萘脲衍生物為彼等其中 X代表裝計線經濟部智慧財產局員工消費合作社印製 20R or 20 R4 R1 R1, R2 and R3 each independently represent hydrogen, halogen, hydroxy, nitro, weyl, amine, Ci_6 alkyl, bis (Ci_6 alkyl) amino, c3_8 cycloalkylamino, Cw alkyl Oxycarbonyl-10- This paper size is in accordance with Chinese National Standard (CNS) A4 (210x297 mm) 200404052 A7 B7 V. Description of the invention (9) 10 15 base, phenyl, benzyl, continuum, Cm alkylamine Base, carbamoyl, K6 alkyl carbamoyl, cyano, cyano Cl_6 alkylamine alkoxy or mono-, di- or alkyl, if necessary mono-, di-bite-Cl -6 generation of Cl-6 alkoxy group, phenoxy group substituted phenoxy group as required, or phase C! · 6 J now requires a mono-, mono- or di-substituted Cl_6 environment hard group. R4 , R5, R6, and R7 each independently represent or a phenyl group; fluorenyl group Z1 represents hydrogen or a Cw alkyl group; and Z2 represents argon, a halogen, or a Cw alkyl group. The hydroxy-tetrahydronaphthyl urea derivative of formula (I), its tautomeric and stereoisomeric forms, and its salts exhibit superior VR1 capture activity. Therefore, it is particularly suitable for the prevention and treatment of diseases related to VR1 activity, specifically for the treatment of acute urinary incontinence and / or overactive bladder. The better ones are hydroxy_tetrahydro-naphthyl urea derivatives of formula (I). Among them, X represents the packing line. It is printed by the Consumer Cooperative of Intellectual Property Bureau of the Ministry of Economic Affairs. 20

或or

-11- .产紙張尺度適用中_家標準(CNS)A4規格⑽χ 297公爱） 200404052 A7 B7 五、發明說明（10) 其中 Y代表一直接鍵結，或-11-. Applicable paper size _ Home Standard (CNS) A4 size ⑽χ 297 public love) 200404052 A7 B7 V. Description of the invention (10) where Y represents a direct bond, or

RJ 10 15 經濟部智慧財產局員工消費合作社印製 20 R1、R2、與R3分別獨立代表氫、鹵素、羥基、石肖基、叛基、胺基、Ci.6烧胺基、二(Ci-6 烧基）胺基、C3_8環烧胺基、Ci_6烧氧罗炭基、苯基、苯甲基、磺醯胺、CN6烷醯基、Ci_6烧酸基胺基、胺甲酷基、Ci_6烧基胺甲醯基、氰基、可視需要經氰基、 Cm烷氧羰基或單-、二-或三_素取代之 C卜6烷基、可視需要經單-、二-或三鹵素取代之Ci_6烷氧基、可視需要經鹵素或 Cw烷基取代之苯氧基、或可視需要經單_、二-或三齒素取代之Cl_6烷硫基； R4與R5分別獨立代表氫或Cm烷基；且 Z1與Z2分別獨立代表氫。另一項具體實施例中，式(I)羥基-四氫-萘脲衍生物可為彼等其中 X代表 12- .丰紙張尺度適用中國國家標準(CNS)A4規格（210 X 297公釐） 200404052 A7 B7 五、發明說明（11)RJ 10 15 Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs 20 R1, R2, and R3 independently represent hydrogen, halogen, hydroxyl, Shi Xiaoji, renyl, amine, Ci. 6 amine, and bis (Ci-6 Group) amine group, C3_8 cycloalkylamino group, Ci_6 alkyloxy carbon group, phenyl, benzyl, sulfonamide, CN6 alkylfluorenyl group, Ci_6 alkylamino group, carbamoyl group, Ci_6alkyl group Formamyl, cyano, optionally substituted C6 alkyl with cyano, Cm alkoxycarbonyl, or mono-, di-, or trisine, and optionally substituted Ci-6 alkyl with mono-, di-, or tri-halogen Phenyloxy, phenoxy substituted with halogen or Cw alkyl, or Cl_6 alkylthio substituted with mono-, di-, or tridentin if necessary; R4 and R5 each independently represent hydrogen or Cm alkyl; and Z1 and Z2 each independently represent hydrogen. In another specific embodiment, the hydroxy-tetrahydro-naphthyl urea derivatives of the formula (I) may be those in which X represents 12-. The paper size is applicable to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) 200404052 A7 B7 V. Description of Invention (11)

其中 Y代表一直接鍵結，或 R5 10 士 R1、R2、與R3分別獨立代表氫、鹵素、二(Cw 烷基）胺基、C3_8環烷胺基、Cw烷氧羰基、可視需要經氰基、Cw烷氧羰基或 15 單-、二-或三鹵素取代之Cw烷基、可視經濟部智慧財產局員工消費合作社印製需要經單-、二-或三鹵素取代之Cu烷氧基、可視需要經鹵素或Ci_6烷基取代之苯氧基、或可視需要經單-、二-或三鹵素取代之Ci_6烧硫基， 20 R4與R5分別獨立代表氫；且 Z1與Z2分別獨立代表氫。另一項具體實施例中，式(I)羥基-四氫-萘脲衍生物可為彼等其中 X代表 -13- 本紙張尺度適用中國國家標準(CNS)A4規格（210x297公釐） 200404052 A7 B7 經濟部智慧財產局員工消費合作社印製五、發明說明（I2Where Y represents a direct bond, or R5 10 ± R1, R2, and R3 each independently represent hydrogen, halogen, di (Cw alkyl) amino, C3-8 cycloalkylamino, Cw alkoxycarbonyl, and optionally cyano through , Cw alkoxycarbonyl or 15 mono-, di-, or tri-halogen substituted Cw alkyl, printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs, which requires mono-, di-, or tri-halogen substituted Cu alkoxy, visual A phenoxy group substituted with a halogen or Ci_6 alkyl group, or a Ci_6 alkylthio group substituted with a mono-, di-, or tri-halogen group if necessary, 20 R4 and R5 each independently represent hydrogen; and Z1 and Z2 each independently represent hydrogen. In another specific embodiment, the hydroxy-tetrahydro-naphthyl urea derivatives of the formula (I) may be those in which X represents -13- This paper size is applicable to the Chinese National Standard (CNS) A4 specification (210x297 mm) 200404052 A7 B7 Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs V. Invention Description (I2

-R3 其中 Y代表一直接鍵結，或 10 15 20-R3 where Y represents a direct bond, or 10 15 20

R 其中 R1與R2分別獨立代表氫、氯、溴、氟、環戊胺基、三氟甲基或三氟甲氧基； R3、R4與R5分別代表氫；且 Z1與Z2分別代表氫。另一項具體實施例中，式(I)羥基-四氫-萘脲衍生物可為彼等其中 X代表R wherein R1 and R2 each independently represent hydrogen, chlorine, bromine, fluorine, cyclopentylamino, trifluoromethyl or trifluoromethoxy; R3, R4 and R5 respectively represent hydrogen; and Z1 and Z2 each represent hydrogen. In another specific embodiment, the hydroxy-tetrahydro-naphthyl urea derivative of formula (I) may be one of them, wherein X represents

-14- 本紙張尺度適用中國國家標準(CNS)A4規格（210 X 297公釐） 10 經濟部智慧財產局員工消費合作社印製 200404052 五、發明說明（13 其中 Y代表一直接鍵結，或 R5 R4 其中 R與R分別獨立代 3 f、三氟甲基=:、甲=、氟、環戊胺 R3、R4與R5分別代表氫；且 Z1與Z2分別代表氫。-14- This paper size is in accordance with Chinese National Standard (CNS) A4 (210 X 297 mm) 10 Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs, 200404052 V. Invention Description (13 where Y represents a direct bond, or R5 R4 wherein R and R independently represent 3 f, trifluoromethyl = :, methyl =, fluorine, cyclopentylamine R3, R4 and R5 represent hydrogen respectively; and Z1 and Z2 represent hydrogen respectively.

更佳者，該式⑴經基·四氫-萘踩衍生物係選自下列各物組成之群中： H N-[4-氣冬(三氟甲基)苯基]_Ν，分經基_5,6,7,8_四氯核基 15 脲；矿、土 Ν-(3_氯苯基)-Ν’-(7-羥基_5,6,7,8-四氫小萘基)脲； Ν_(7-羥基-5,6,7,8-四氫小萘基)-Ν，_[3_(三氟甲基）苯基]脲； Ν-(7-羥基-5,6,7,8-四氫-1-萘基)^^^三氟甲基）苯基]脲； 3-({[〇羥基-5,6,7,8-四氫-μ萘基)胺基]羰基}胺基)苯甲酸乙 20 酯； Ν-(7-羥基-5,6,7,8_四氫小萘基)-1^’-(1-萘基)脲； Ν-(7-^ 基-5,6,7,8-四氫-1-萘基)-Ν’-(2-萘基)腺； Ν-(3,4-二氣苯基)-Ν，-(7-羥基-5,6,7,8-四氫小萘基)脲； N-(7-^i基-5,6,7,8-四氫-1-萘基)-Ν’-(4-異丙基笨基）脲； -15· 本紙張尺度適用中國國家標準(CNS)A4規格（210x297公釐）More preferably, the hydrazine-tetrahydro-naphthalene derivative is selected from the group consisting of: H N- [4-Gasonia (trifluoromethyl) phenyl] _N, a warp group _5,6,7,8_tetrachloronuclear 15 urea; ore, soil N- (3-chlorophenyl) -N '-(7-hydroxy_5,6,7,8-tetrahydro small naphthyl ) Urea; Ν_ (7-hydroxy-5,6,7,8-tetrahydrosmallnaphthyl) -N, _ [3_ (trifluoromethyl) phenyl] urea; Ν- (7-hydroxy-5,6 , 7,8-tetrahydro-1-naphthyl) ^^^ trifluoromethyl) phenyl] urea; 3-({[〇hydroxy-5,6,7,8-tetrahydro-μnaphthyl) amine Yl] carbonyl} amino) ethyl 20 benzoate; Ν- (7-hydroxy-5,6,7,8-tetrahydrosmallnaphthyl) -1 ^ '-(1-naphthyl) urea; Ν- ( 7-^-5,6,7,8-tetrahydro-1-naphthyl) -N '-(2-naphthyl) gland; Ν- (3,4-diaminophenyl) -N,-( 7-hydroxy-5,6,7,8-tetrahydrosmallnaphthyl) urea; N- (7- ^ i-5-5,6,7,8-tetrahydro-1-naphthyl) -N '-( 4-Isopropylbenzyl) urea; -15 · This paper size applies to China National Standard (CNS) A4 (210x297 mm)

經濟部智慧財產局員工消費合作社印製 200404052 A7 B7 五、發明說明（Η) Ν-(7-經基-5,6,7,8-四鼠-1-姜基)-NL(4-苯氧基苯基)脱； N-[4_氯-3-(三氟甲基）苯基]-N’-(7_羥基-5,6,7,8-四氫-1-萘基) 脈； N-[4-氯-3-(三氟甲基）苯基]-Nf-[(7S)-7-羥基-5,6,7,8-四氬小 5 萘基]脲； N-[4-氯-3-(三氟甲基）苯基-N’-[(7R)-7-羥基-5,6,7,8-四氫小萘基]脲； 1^-(7-經基-5,6,7,8-四氮-1-奈基)-N’-苯基躲·， N-(4-氯苯基)-N’-(7_羥基-5,6,7,8-四氫小萘基)脲； 10 N-(7-^基-5,6,7,8-四鼠-1-奈基)-N’-[2-(二氣曱基）苯基]腺， N-(7-羥基-5,6,7,8-四氫-1-萘基)-N’-[4-(三氟甲基)苯基]脲； N_(3,4-二氯苯基)-N’-(7-羥基-5,6,7,8-四氫小萘基)脲； N_(7-羥基-5,6,7,8-四氫小萘基>^’-[4-(三氟曱氧基）苯基] 脲； 15 N-(7-經基-5,6,7,8-四氫-1-萘基)-Nf-[4-(三氟甲氧基）苯曱基] 脲； N-(7-羥基-5,6,7,8 -四氫-1 -萘基)^-(2,4,6-三甲氧苯甲基) 脲； N-(2,6-二氟苯甲基)-N47-羥基-5,6,7,8-四氫小萘基)脲； 20 N-[(7R)-7-羥基-5,6,7,8-四氫小萘基]-^-[4-(三氟甲基）苯曱基]腺， N_[(7S)-7-羥基-5,6,7,8-四氫-1-萘基]-N’-[4-(三氟甲基)-苯甲基]脲； N-[(7R)-7-羥基·5,6,7,8-四氫-1-萘基]-N’-[4-(三氟曱氧基)-苯 -16- 本紙張尺度適用中國國家標準(CNS)A4規格（210x297公釐）Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs, 200404052 A7 B7 V. Description of the Invention (Η) Ν- (7- 经基 -5,6,7,8- 四鼠 -1- 姜基) -NL (4-benzene Oxyphenyl) deoxy; N- [4-chloro-3- (trifluoromethyl) phenyl] -N '-(7_hydroxy-5,6,7,8-tetrahydro-1-naphthyl) Vein; N- [4-chloro-3- (trifluoromethyl) phenyl] -Nf-[(7S) -7-hydroxy-5,6,7,8-tetra-argon small 5 naphthyl] urea; N -[4-chloro-3- (trifluoromethyl) phenyl-N '-[(7R) -7-hydroxy-5,6,7,8-tetrahydrosmallnaphthyl] urea; 1 ^-(7 -Ethyl-5,6,7,8-tetraaza-1-naphthyl) -N'-phenylhexyl, N- (4-chlorophenyl) -N '-(7-hydroxy-5,6 , 7,8-tetrahydrosmallnaphthyl) urea; 10 N- (7- ^ yl-5,6,7,8-tetramus-1-naphthyl) -N '-[2- (diaziridinyl) ) Phenyl] gland, N- (7-hydroxy-5,6,7,8-tetrahydro-1-naphthyl) -N '-[4- (trifluoromethyl) phenyl] urea; N_ (3 , 4-dichlorophenyl) -N '-(7-hydroxy-5,6,7,8-tetrahydro small naphthyl) urea; N_ (7-hydroxy-5,6,7,8-tetrahydro small Naphthyl > ^ '-[4- (trifluorofluorenyloxy) phenyl] urea; 15 N- (7-Cyclo-5,6,7,8-tetrahydro-1-naphthyl) -Nf- [4- (trifluoromethoxy) phenylfluorenyl] urea; N- (7-hydroxy-5,6,7,8-tetrahydro-1 -naphthyl) ^-(2,4,6-trimethoxy Benzyl) urea; N- (2,6-di Benzyl) -N47-hydroxy-5,6,7,8-tetrahydro small naphthyl) urea; 20 N-[(7R) -7-hydroxy-5,6,7,8-tetrahydro small naphthyl ]-^-[4- (trifluoromethyl) phenylfluorenyl] gland, N _ [(7S) -7-hydroxy-5,6,7,8-tetrahydro-1-naphthyl] -N '-[ 4- (trifluoromethyl) -benzyl] urea; N-[(7R) -7-hydroxy · 5,6,7,8-tetrahydro-1-naphthyl] -N '-[4- ( Trifluorofluorenyloxy) -benzene-16- This paper size is applicable to China National Standard (CNS) A4 (210x297 mm)

200404052 五、發明說明（η) 甲基]踩； N-[(7S)_7_減_5,6,7,8_四氫萘基]抓[4(三氟甲氧基乂苯甲基]脲； N-[2-(4_氯苯基）乙基]_N，_⑽基.如㈣氫丄萘基鹰； 5 與 N-[3_貌-4_(二氟曱基）笨甲基]抓(7_經基_5,6,7,8_四氣小笑基)脲。不本發明内文中，取代基若未另外說明時，通常如下列定義： 10 烷基本身與烷氧基 '烷醯基、烷胺基、烷胺羰基、烷胺石黃醯基、烧石黃醯胺基、烧氧縣、烧氧_基及烧醯胺基中之”烷”與”烷基”代表一般具有丨_6個碳原子(較佳為卜 4個，特別佳為1-3個)之直鏈或分支烷基，其較佳代表性實例為曱基、乙基、正丙基、異丙基、第三丁基、正戊基 15 與正己基。烷氧基之較佳代表性實例為甲氧基、乙氧基、正丙氧基、異丙氧基、第三丁氧基、正戊氧基與正己氧基。烧醯基之較佳代表性實例為乙醯基與丙醯基。經濟部智慧財產局員工消費合作社印製烷胺基代表具有一或兩個（分別獨立選自）烷基取代基 20之烷胺基，其較佳代表性實例為甲胺基、乙胺基、正丙胺基、異丙胺基、第三丁胺基、正戊胺基、正己胺基、Ν，Ν-一甲胺基、Ν，Ν-二乙胺基、Ν-乙基甲胺基、Ν-甲基-Ν-正丙胺基、Ν-異丙基正丙胺基、Ν-第三丁基-Ν-甲胺基、Ν_乙基-Ν-正戊胺基與泳正己基县甲胺基。 -17- 張尺度適Ϊ中國國家標準(CNS)A4羯$Γ(21〇 χ 297公釐） --- 200404052 A7 B7 五、發明說明（16) 10 15 經濟部智慧財產局員工消費合作社印製 20 烷胺羰基或烷基胺甲醯基代表具右 ^ 育一或兩個（分別獨立選自）烷基取代基之烷胺羰基，其較佶处+ — 千又佳代表性實例為甲胺羰基、乙胺羰基、正丙胺羰基、異丙胺羰基、第三丁胺幾基、正戊贿基、正己胺絲、恤二甲職基、NN_ 二乙胺幾基、N-乙基善甲胺減、㈠基善正丙胺幾基、N-異丙基-N-正丙胺幾基、N_第三丁基_N_甲胺羰基、 N-乙基-N-正戊胺羰基與N_正己基·Ν_甲胺羰美。烷氧羰基之較佳代表性實例為甲氧羰基、乙氧羰基、正丙氧Μ基、異丙氧、第三丁氧縣、正戊氧幾基與正己氧羰基。烧氧羰胺基之較佳代表性實例為甲氧羰胺基、乙氧羰胺基、正丙氧羰胺基、異丙氧羰胺基、第三丁氧羰胺基、正戊氧羰胺基與正己氧羰基。烷醯胺基之較佳代表性實例為乙醯胺基與乙羰胺基。環烷基本身與環烷胺基及環烷羰基中之環烷基代表具有3-8個碳原子（以5-7個較佳）之環烷基，其較佳代表性貫例為環丙基、環丁基、環戊基、環己基與環庚基。環烷胺基代表具有一或兩個（分別獨立選自）環烷基取代基之環烷胺基，其較佳代表性實例為環丙胺基、環丁胺基、％戊胺基、環己胺基與環庚胺基。鹵素代表氟、氣、溴與碘。 ^較佳者，本發明之醫藥尚包含一種或多種醫藥上可接受之載劑與/或賦形劑。式(I)羥基-四氫-萘脲衍生物、其互變異構型與立體異構型、及其鹽可有效治療或預防選自下列各物組成之群中 -18- 产纸張尺度適財關家標準(CNS)A4祕^^ ά 計線 200404052 A7 B7 五、發明說明 17 10 15 經濟部智慧財產局員工消費合作社印製 20 之疾病：尿急性尿失禁、過度活性膀胱、慢性疚、病變性疼痛、手術後疼痛、類風濕_炎 1、神麵神經病變、痛《、神經受傷、絕血、神神，痛、風，及發炎疾病如：氣喘及c〇pD，因為此 /、/或中活性有關。疾病與v：^ 該等化合物亦可用於治療及預防神經病變係一種經常與帶狀疱疹及疱疹後神經痛有關疼痛（其式）、疼痛之糖尿病性神經病變、神經病變二之=痛形痛、創傷後與手術後神經痛、因神經壓迫彳丨起下q部疼其他神經痛、幻想痛、複合性局部疼痛症候蛘、神經痛及副傳染性神經病變，如彼等與HIV感染有關者，傳杂性或經系統病變有關之疼痛，如：多發性硬化或巴金，中柩神脊柱受傷或創傷性腦部受傷，及中風後疼痛。〃株氏症或此外，該等化合物適用於治療骨骼肌肉疼广種經常與骨關節炎或類風溼關節炎或其他型式=_ ( =，一關之疼痛形式)與背部疼痛。 ]節戈有此外，該等化合物適用於治療與癌症有關之疼痛勺括與癌症或癌症治療有關之内臟疼痛或神經病變性疼痛。該等化合物亦適用於治療内臟疼痛，例如：與中空内臟阻塞有關之疼痛，如：膽結减痛、與刺激性腸部症候群有關之疼痛、骨盆腔疼痛、女陰部疼痛、睪丸痛或前列腺痛。該等化合物亦適用於治療與關節、皮膚、肌肉或神經之發炎損傷有關之疼痛。 19- 本紙張尺度適用中國國家標準(CNS)A4規格（210x297公釐） 200404052 Α7 Β7 五、發明說明（18) 該等化合物適用於治療口筋膜疼痛與頭痛，例如：偏頭痛或緊張型頭痛。實施方式 5 本發明式⑴化合物可依（但不限於）下列方法[A]、 [B]、[C]、[D]、[E]、[F]或[G]製備。有些具體實施例中，作為起始物或中間物之化合物中一個或多個取代基，如：胺基、羧基與羥基宜使用習此相關技藝之人士已知之保護基保護。保護基實例說明於Greene與Wuts著之 10 ’’Protective Groups in Organic Synthesis (第三版）’’，紐約 John Wiley and Sons 出版0 [方法A] 15200404052 V. Description of the invention (η) methyl] step; N-[(7S) _7_minus_5,6,7,8_tetrahydronaphthyl] [4 (trifluoromethoxypyridyl)] Urea; N- [2- (4-chlorophenyl) ethyl] _N, _fluorenyl. Such as fluorinated naphthyl halide; 5 and N- [3_N-4_ (difluorofluorenyl) benzylmethyl] (7-Cycloyl-5,6,7,8_tetrakismyl) urea. Not in the context of the present invention, unless otherwise specified, the substituent is usually defined as follows: 10 Alkyl itself and alkoxy "Alkyl" and "alkyl" in alkylamine, alkylamino, alkylamine carbonyl, alkylamine stilbene, sulphuric acid stilbene amine, sulphate oxygen, sulphonyl group and stilbene amine group represent general A linear or branched alkyl group having 6 carbon atoms (preferably 4 carbon atoms, particularly preferably 1 to 3 carbon atoms). The preferred representative examples are fluorenyl, ethyl, n-propyl, isopropyl Base, third butyl, n-pentyl 15 and n-hexyl. Preferred representative examples of alkoxy are methoxy, ethoxy, n-propoxy, isopropoxy, third butoxy, n- Pentyloxy and n-hexyloxy. The better representative examples of stilbene are ethenyl and propionyl. Employees at the Intellectual Property Bureau of the Ministry of Economic Affairs ’consumption The alkylamine group printed by the company represents an alkylamino group having one or two (respectively independently selected) alkyl substituents of 20. The preferred representative examples are methylamino, ethylamino, n-propylamino, isopropylamine , Tertiary butylamino, n-pentylamino, n-hexylamino, N, N-monomethylamino, N, N-diethylamino, N-ethylmethylamino, N-methyl-N-n- Propylamino, N-isopropyl-n-propylamino, N-tertiary-butyl-N-methylamino, N-ethyl-N-n-pentylamino and n-hexyl methylamine. -17- Zhang scale Applicable to China National Standard (CNS) A4 羯 Γ (21〇χ 297 mm) --- 200404052 A7 B7 V. Description of the invention (16) 10 15 Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs 20 Alkyl carbonyl or Alkylamine formamyl represents an alkylamine carbonyl group with one or two (respectively independently selected) alkyl substituents, which are better than ++ — Representative examples are methylamine carbonyl and ethylamine carbonyl , N-propylamine carbonyl, isopropylamine carbonyl, tert-butylamine, n-pentylbranyl, n-hexylamine silk, dimethylamine, NN_diethylamine, N-ethylsulfanylamine, fluorenylsulfonyl Propylamine, N- Propyl-N-n-propylamine chinyl, N-third butyl_N_methylamine carbonyl, N-ethyl-N-n-pentylamine carbonyl and N_n-hexyl · N_methylamine carbamyl. Alkoxycarbonyl The preferred representative examples are methoxycarbonyl, ethoxycarbonyl, n-propoxy M, isopropoxy, tertiary butoxy, n-pentyloxy and n-hexyloxycarbonyl. Better representatives of oxycarbonylamino Exemplary examples are methoxycarbonylamino, ethoxycarbonylamino, n-propoxycarbonylamino, isopropyloxycarbonylamino, tertiary butoxycarbonylamino, n-pentoxycarbonylamino and n-hexyloxycarbonyl. Preferred representative examples of the amino group are acetoamino and acetoamino. The cycloalkyl group itself and the cycloalkyl group in the cycloalkylamino group and the cycloalkylcarbonyl group represent a cycloalkyl group having 3 to 8 carbon atoms (preferably 5 to 7), and a preferred representative example thereof is cyclopropyl Base, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl. The cycloalkylamino group represents a cycloalkylamino group having one or two (respectively independently selected) cycloalkyl substituents, and preferred representative examples thereof are cyclopropylamino, cyclobutylamino,% pentylamino, cyclohexyl Amine and cycloheptylamino. Halogen stands for fluorine, gas, bromine and iodine. Preferably, the medicament of the present invention further comprises one or more pharmaceutically acceptable carriers and / or excipients. The hydroxy-tetrahydro-naphthyl urea derivative of formula (I), its tautomeric and stereoisomeric forms, and salts thereof can effectively treat or prevent the group selected from the group consisting of Secret of Financial Standards (CNS) A4 ^^ ά Line 200404052 A7 B7 V. Invention Description 17 10 15 Diseases printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs 20 Diseases: acute urinary incontinence, overactive bladder, chronic guilt, Pathological pain, postoperative pain, rheumatoid inflammation_1, facial neuropathy, pain ", nerve injury, hemostasis, Shenshen, pain, wind, and inflammatory diseases such as asthma and copD, because of this, And / or moderate activity. Diseases and v: ^ These compounds can also be used to treat and prevent neuropathy, a type of pain often associated with shingles and postherpetic neuralgia (the formula), painful diabetic neuropathy, and neuropathy two = painful pain , Post-traumatic and post-operative neuralgia, neuralgia due to nerve compression, other neuralgia, fantasy pain, compound local pain syndrome, neuralgia and parainfectious neuropathy, such as those related to HIV infection Pain associated with heterogeneous or systemic diseases, such as: multiple sclerosis or barking, spinal injury or traumatic brain injury in the midbrain, and pain after stroke. Bacillus or In addition, these compounds are suitable for treating a wide range of musculoskeletal pains. They are often associated with osteoarthritis or rheumatoid arthritis or other types of pain (=, a related form of pain) and back pain. ] Jie Geyou In addition, these compounds are suitable for the treatment of cancer-related pain, including visceral pain or neuropathic pain associated with cancer or cancer treatment. The compounds are also suitable for the treatment of visceral pain, such as pain associated with hollow visceral obstruction, such as: biliary pain reduction, pain associated with irritable bowel syndrome, pelvic pain, genital pain, testicular pain, or Prostate pain. These compounds are also suitable for the treatment of pain associated with inflammatory damage to joints, skin, muscles or nerves. 19- This paper size is in accordance with Chinese National Standard (CNS) A4 (210x297 mm) 200404052 Α7 Β7 V. Description of the invention (18) These compounds are suitable for the treatment of oral fascia pain and headache, such as migraine or tension headache . Embodiment 5 The compound of formula (I) of the present invention can be prepared according to the following methods [A], [B], [C], [D], [E], [F] or [G]. In some embodiments, one or more substituents in the compound as a starting material or an intermediate such as: amine group, carboxyl group and hydroxyl group should be protected by protecting groups known to those skilled in the art. Examples of protecting groups are illustrated in Greene and Wuts. 10 ’’ Protective Groups in Organic Synthesis (Third Edition) ’, published by John Wiley and Sons, New York 0 [Method A] 15

OCN. (ill) 、xOCN. (Ill), x

X ⑴ 經濟部智慧財產局員工消費合作社印製 20 式(I)化合物（其中x、z1與z2如上述定義）之製法可由式(II)化合物（其中Z1與Z2如上述定義）與異氰酸酯(111)(其中X如上述定義）反應。該反應可於溶劑中進行，包括例如：鹵化烴，如：二 -20- 本紙張尺度適用中國國家標準(CNS)A4規格（210x297公釐） 200404052 A7 10 15 發明說明（19) 氯甲烷、氯仿與1，2-二氯乙烷；醚類，如··***、異丙醚、二哼烷與四氫呋喃（丁 HF)及丨，2•二甲氧乙烷；芳香丈二如·笨、甲笨與二甲苯；腈類，如··乙腈；醯胺類，如· N，N-二甲基甲醯胺qmf)、N，N•二甲基乙醯胺 (DMAC)與N-甲基吡咯烧酮(NMP);脲類，如：以工甲基咪唑啶酮(DMI);亞砜類，如：二甲亞砜(DMSO);等專。可視需要混合使用選自上列兩種或多種溶劑。該反應可於有機驗之存在下進行，如：σ比唆或三乙胺。反應溫度可視需要依據進行反應之化合物設定。反應溫度通常（但不限於）約室溫至1〇〇。(3。該反應通常可進行 30分鐘至48小時，較佳為U4小時α 式(Π)化合物與異氰酸酯(III)可自商品取得或可依已知技術製備。[方法B] 經濟部智慧財產局員工消費合作社印製X ⑴ Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs 20 Compounds of formula (I) (where x, z1 and z2 are as defined above) can be prepared by compounds of formula (II) (where Z1 and Z2 are as defined above) ) (Where X is as defined above). The reaction can be carried out in a solvent, including, for example: halogenated hydrocarbons, such as: 2-20- This paper size is applicable to Chinese National Standard (CNS) A4 (210x297 mm) 200404052 A7 10 15 Description of the invention (19) Methyl chloride, chloroform With 1,2-dichloroethane; ethers, such as ether, isopropyl ether, dihumane and tetrahydrofuran (butane HF) and 丨, 2 • dimethoxyethane; aromatic dioxin, stupid, stupid With xylene; nitriles, such as acetonitrile; ammonium, such as N, N-dimethylformamide (mfm), N, N • dimethylacetamide (DMAC), and N-methylpyrrole Burning ketones (NMP); ureas, such as: Methylimidazolidone (DMI); sulfoxides, such as: dimethyl sulfoxide (DMSO); etc. If necessary, two or more solvents selected from the above may be mixed and used. The reaction can be performed in the presence of organic test, such as: σ than 唆 or triethylamine. The reaction temperature may be set according to the compound to be reacted as required. The reaction temperature is usually (but not limited to) about room temperature to 100. (3. The reaction can usually be carried out for 30 minutes to 48 hours, preferably U4 hours. The alpha compound (Π) and isocyanate (III) can be obtained from commercial products or can be prepared according to known techniques. [Method B] Intellectual Property of the Ministry of Economic Affairs Printed by the Bureau's Consumer Cooperative

光氣，二光氣，三光氣， CDI 或 CDT 〇 Λ HN /X η2ν (IV)Phosgene, diphosgene, triphosgene, CDI or CDT 〇 Λ HN / X η2ν (IV)

⑴ 式⑴化合物（其中X、ζ1與Ζ2如上述定義）之製法可由式(II)化合物(其中Ζ1與Ζ2如上述定義)與光氣、二光氣、 -21- 本紙張尺度適用中國國家標準(CNS)A4規格（2ΐ〇χ297公釐） 200404052 A7 _____B7 五、發明說明（2〇 ) 三光氣、1，1-羰基二咪嗤（CDI)或1，1’-幾基二二唑)(CDT)反應，然後添加式(IV)化合物（其中X如上述定義）至反應混合物中。該反應可於溶劑中進行，包括例如：鹵化烴，如：二 5 氣甲烷、氣仿與1，2-二氣乙烷；醚類，如：***、異丙醚、二啐烷與四氫呋喃（THF)及1，2-二甲氧乙烷；芳香烴，如：苯、甲苯與二甲苯；腈類，如：乙腈；醯胺類，如：N，N-二甲基甲醯胺(DMF)、N，N-二甲基乙醯胺 (DMAC)與N_甲基吡咯烷酮(NMP);脲類，如：1，3_二甲 10基-2-咪唑啶酮〇DMI);等等。可視需要混合使用選自上列兩種或多種溶劑。反應溫度可視需要依據進行反應之化合物設定。反應溫度通常（但不限於）約2(TC至5〇r ^該反應通常可進行 30分鐘至10小時，較佳為ι_24小時。 15 光氣、二光氣、三光氣、CDI與CDT可自商品取得，且式(IV)化合物可自商品取得或可依已知技術製備。 [方法C]⑴ The compound of formula (where X, ζ1 and Z2 are as defined above) can be prepared by the compound of formula (II) (where Z1 and Z2 are as defined above) and phosgene, diphosgene, -21 (CNS) A4 specification (2 ×× 297 mm) 200404052 A7 _____B7 V. Description of the invention (2) Triphosgene, 1,1-carbonyldiimidazine (CDI) or 1,1'-chididiazole) ( CDT) reaction, and then a compound of formula (IV) (wherein X is as defined above) is added to the reaction mixture. The reaction can be carried out in a solvent, including, for example: halogenated hydrocarbons, such as: di-5 methane, gas-form, and 1,2-digas ethane; ethers, such as: diethyl ether, isopropyl ether, dioxane, and tetrahydrofuran ( THF) and 1,2-dimethoxyethane; aromatic hydrocarbons, such as: benzene, toluene, and xylene; nitriles, such as: acetonitrile; amidoamines, such as: N, N-dimethylformamide (DMF ), N, N-dimethylacetamide (DMAC) and N-methylpyrrolidone (NMP); ureas, such as: 1,3-dimethyl-10yl-2-imidazolidinone (DMI); etc. . If necessary, two or more solvents selected from the above may be mixed and used. The reaction temperature may be set according to the compound to be reacted as required. The reaction temperature is usually (but not limited to) about 2 ° C to 50 ° C. The reaction can usually be performed for 30 minutes to 10 hours, preferably ι_24 hours. 15 Phosgene, diphosgene, triphosgene, CDI and CDT can be Commercially available, and compounds of formula (IV) can be obtained from commercial products or can be prepared according to known techniques. [Method C]

200404052 A7 B7 五、發明說明（21) 式⑴化合物（其中X、Z1與Z2如上述定義）之製法可由式(II)化合物(其中Z1與Z2如上述定義)與式(V)化合物(其中L!代表鹵原子，如：氯、溴或蛾原子）反應，然後添加式(IV)化合物（其中X如上述定義）至反應混合物中。 5 該反應可於溶劑中進行，包括例如：i化烴，如：二氣甲烧、氣仿與1，2-二氯乙烧；趟類，如：***、異丙醚、二畤烷與四氫呋喃（THF)及1，2-二甲氧乙烷；芳香烴，如··苯、甲苯與二甲苯；腈類，如：乙腈；醯胺類，如：N，N_二曱基曱醯胺(DMF)、n，N-二甲基乙醯胺 10 (DMAC)與N-甲基吡咯烷酮(NMP);脲類，如：1，3_二甲基-2-咪唑啶酮(DMI);等等。可視需要混合使用選自上列兩種或多種溶劑。反應溫度可視需要依據進行反應之化合物設定。反廡溫度通常（但不限於）約如它至12(rc。該反應通常可進ς 15 卜48小時，較佳為2-24小時。該反應宜於驗之存在下進行，包括例如：有機胺類，如：啦咬、三乙胺與Ν，Ν-二異丙基乙胺、二甲基笨胺、二乙基笨胺、4-二甲胺基咣咬，等等。經濟部智慧財產局員工消費合作社印製化合物(V)可自商品取得或可依已知技術製備。 20 [方法D] -23- 本紙張尺度適財目國ϋ準(CNS)A4規格(21〇X297;Jy 200404052 A7 B7 (22) 五、發明說明200404052 A7 B7 V. Description of the invention (21) The compound of formula (where X, Z1 and Z2 are as defined above) can be prepared by the compound of formula (II) (where Z1 and Z2 are as defined above) and the compound of formula (V) (wherein L ! Represents a halogen atom, such as: chlorine, bromine or moth atom, and then a compound of formula (IV) (where X is as defined above) is added to the reaction mixture. 5 The reaction can be carried out in a solvent, including, for example, hydrogenated hydrocarbons, such as: digas methylbenzene, gas imitation, and 1,2-dichloroethane; cyanide, such as: ether, isopropyl ether, dioxane and Tetrahydrofuran (THF) and 1,2-dimethoxyethane; aromatic hydrocarbons, such as benzene, toluene, and xylene; nitriles, such as: acetonitrile; amidoamines, such as: N, N_difluorenylfluorene Amine (DMF), n, N-dimethylacetamide 10 (DMAC) and N-methylpyrrolidone (NMP); ureas, such as: 1,3-dimethyl-2-imidazolidinone (DMI) ;and many more. If necessary, two or more solvents selected from the above may be mixed and used. The reaction temperature may be set according to the compound to be reacted as required. The reaction temperature is usually (but not limited to) about it to 12 (rc.) The reaction can usually be carried out for 15 to 48 hours, preferably 2 to 24 hours. The reaction is preferably carried out in the presence of a test, including, for example, organic Amines, such as: bites, triethylamine and Ν, Ν-diisopropylethylamine, dimethylbenzylamine, diethylbenzylamine, 4-dimethylaminopyridine, etc. Wisdom of the Ministry of Economic Affairs The compound (V) printed by the Consumer Cooperative of the Property Bureau can be obtained from the commodity or can be prepared according to known techniques. 20 [Method D] -23- This paper is suitable for the national standard (CNS) A4 specification (21〇297; Jy 200404052 A7 B7 (22) V. Description of the invention

5 /X h2n (IV) 10 式(I)化合物（其中X、Z1與Z2如上述定義）之製法可由式(IV)化合物（其中X如上述定義）與光氣、二光氣、三光氣、1，1-羰基二咪唑(CDI)或1，Γ-羰基二（1，2,4-***)(CDT) 反應，然後添加式(II)化合物（其中Z1與Z2如上述定義）至反應混合物中。 15 該反應可於溶劑中進行，包括例如：鹵化烴，如：二經濟部智慧財產局員工消費合作社印製氯甲烷、氯仿與1，2-二氯乙烷；醚類，如：***、異丙醚、二畤烷與四氫呋喃（THF)及1，2-二甲氧乙烷；芳香烴，如：苯、曱苯與二甲苯；腈類，如：乙腈；醯胺類，如：N，N-二甲基曱醯胺（DMF)、N，N-二甲基乙醯胺 20 (DMAC)與N-曱基吡咯烷酮(NMP);脲類，如：1，3-二甲基-2-咪唑啶酮(DMI);亞颯類，如··二甲亞艰(DMSO);等等。可視需要混合使用選自上列兩種或多種溶劑。反應溫度可視需要依據進行反應之化合物設定。反應溫度通常（但不限於）約30°C至l〇〇°C。 -24- 本紙張尺度適用中國國家標準(CNS)A4規格（210x297公釐） 200404052 A7 B7 五、發明說明（23 ) ' -- 該反應通常可進行3〇分鐘至4〇，士 J、時，較佳為1-24 小時。 q [方法E]5 / X h2n (IV) 10 The compound of formula (I) (where X, Z1 and Z2 are as defined above) can be prepared by the compound of formula (IV) (where X is as defined above) and phosgene, diphosgene, triphosgene, 1,1-carbonyldiimidazole (CDI) or 1, Γ-carbonylbis (1,2,4-triazole) (CDT), and then add a compound of formula (II) (wherein Z1 and Z2 are as defined above) to the reaction In the mixture. 15 The reaction can be carried out in a solvent, including, for example: halogenated hydrocarbons, such as: printed methyl chloride, chloroform, and 1,2-dichloroethane printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs; ethers such as ether, isopropyl Propyl ether, dioxane and tetrahydrofuran (THF) and 1,2-dimethoxyethane; aromatic hydrocarbons, such as: benzene, xylene and xylene; nitriles, such as: acetonitrile; ammonium, such as: N, N-dimethylfluorenamine (DMF), N, N-dimethylacetamide 20 (DMAC) and N-fluorenylpyrrolidone (NMP); ureas, such as: 1,3-dimethyl-2 -Imidazolidone (DMI); subfluorinated species, such as DMSO; etc. If necessary, two or more solvents selected from the above may be mixed and used. The reaction temperature may be set according to the compound to be reacted as required. The reaction temperature is usually, but not limited to, about 30 ° C to 100 ° C. -24- This paper size is in accordance with Chinese National Standard (CNS) A4 (210x297 mm) 200404052 A7 B7 V. Description of the invention (23) '-This reaction can usually be carried out for 30 minutes to 40, J, H, It is preferably 1-24 hours. q [Method E]

經濟部智慧財產局員工消費合作社印製式⑴化合物(其中χ、Ζι與z2如上述定義)之製法可由式(IV)化合物（其中X如上述定義）與式(v)化合物（其中 15 代表鹵原子，如：氣、溴或碘原子）反應，然後添加式(II) 化合物（其中Z1與Z2如上述定義）至反應混合物中。該反應可於溶劑中進行，包括例如：鹵化煙，如：二氣甲烷、氯仿與1，2-二氯乙烷；醚類，如：***、異丙醚、二畤烷與四氫呋喃（THF)& 12-二甲氧乙烷；芳香 20 烴，如：苯、甲苯與二甲苯；腈類，如··乙腈；醯胺類，如·· N，N_二曱基曱醯胺(DMF)、N，N-二甲基乙醯胺(DMAC) 與N-甲基吡咯烷酮(NMP);脲類，如：1，3-二甲基-2-咪唑啶酮(DMI);等等。可視需要混合使用選自上列兩種或多種溶劑。 -25- 本纸張尺度適用中國國家標準(CNS)A4規格（210 X 297公釐） 200404052The method of printing formula ⑴ compounds (where χ, Zι, and z2 are as defined above) printed by employees' cooperatives of the Intellectual Property Bureau of the Ministry of Economics can be prepared by compounds of formula (IV) (where X is defined above) and compounds of formula (v) (where 15 represents halogen Atoms such as gas, bromine or iodine are reacted, and then a compound of formula (II) (wherein Z1 and Z2 are as defined above) is added to the reaction mixture. This reaction can be carried out in a solvent, including, for example: halogenated fume, such as: digas methane, chloroform, and 1,2-dichloroethane; ethers, such as: ether, isopropyl ether, dioxane, and tetrahydrofuran (THF) &12-dimethoxyethane; aromatic 20 hydrocarbons, such as: benzene, toluene, and xylene; nitriles, such as acetonitrile; ammoniums, such as N, N_difluorenylamine (DMF ), N, N-dimethylacetamide (DMAC) and N-methylpyrrolidone (NMP); ureas, such as: 1,3-dimethyl-2-imidazolidinone (DMI); and so on. If necessary, two or more solvents selected from the above may be mixed and used. -25- This paper size is applicable to China National Standard (CNS) A4 (210 X 297 mm) 200404052

XX

15 經濟部智慧財產局員工消費合作社印製 A7 B7 五、發明說明（24) 反應溫度可視需要依據進行反應之化合物設定。反應溫度通常（但不限於）約30°C至120°C。該反應通常可進行1-48小時，較佳為2-24小時。該反應宜於鹼之存在下進行，包括例如：有機胺類， 5 如··吡啶、三乙胺與N，N-二異丙基乙胺、二甲基苯胺、二乙基苯胺、4-二甲胺基吡啶，等等。 [方法F] 10 類似方法[A]-[E] ’但 NH2 改用(VI)替代(Π) 步驟F-1 步驟F-2 2015 Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs A7 B7 V. Description of the invention (24) The reaction temperature can be set according to the compound to be reacted. The reaction temperature is usually, but not limited to, about 30 ° C to 120 ° C. This reaction is usually carried out for 1 to 48 hours, preferably 2 to 24 hours. The reaction is suitably carried out in the presence of a base, including, for example: organic amines, such as: pyridine, triethylamine and N, N-diisopropylethylamine, dimethylaniline, diethylaniline, 4- Dimethylaminopyridine, and so on. [Method F] 10 Similar method [A]-[E] ’but NH2 uses (VI) instead of (Π) Step F-1 Step F-2 20

X 步驟F-3 還原劑 (I，） cX Step F-3 Reducing agent (I,) c

-26- 本紙張尺度適用中國國家標準(CNS)A4規格（210 X 297公釐） 200404052 Α7 Β7 五、發明說明（25 〇-26- This paper size is in accordance with Chinese National Standard (CNS) A4 (210 X 297 mm) 200404052 Α7 Β7 V. Description of the invention (25 〇

經濟部智慧財產局員工消費合作社印製式(Γ)化合物（其中X與Z2如上述定義）之製法如下：步驟F-1中，式(VII)化合物（其中X與Z2如上述定義）可類似方法[A]、[B]、[C]、[D]或[E]中製備式⑴化合物之 1〇方法，改用式(VI)化合物（其中Z2如上述定義）替代式(11) 化合物製備。步驟F-2中，式(VIII)化合物(其中X與z2如上述定義）之製法可由式(VII)化合物（其中X與Z2如上述定義）與酸 (如：鹽酸)反應。 15 該反應可於溶劑中進行，包括例如：i化烴，如：二氯甲烷、氣仿與1，2-二氣乙烷；醚類，如：***、異丙醚、二啐烷與四氫呋喃（THF)及1，2-二甲氧乙烷；醇類，如：甲醇'乙醇；水，等等。可視需要混合使用選自上列兩種或多種溶劑。 20 反應溫度可視需要依據進行反應之化合物設定。反應溫度通常（但不限於）約20°C至100。(：。該反應通常可進行 30分鐘至10小時，較佳為1-24小時。步驟F-3中，式(Γ)化合物（其中X與Z2如上述定義）之製法可由式(VIII)化合物（其中X與Z2如上述定義）與還 -27- _本紙張尺度顧㈣國ϋ準(CNS)A4規格⑵0x297公髮）------ 200404052 A7 B7 五、發明說明（26 ) 原劑（如：氫硼化鈉或氫化理鋁）反應。該反應可於溶劑中進行，包括例如：醚類，如：乙醚、異丙醚、二畤烧與四氫呋喃（THF)及1,2-二甲氧乙烷；脂系烴類，如：正己烷、環己烷；芳香烴類，如： 5 苯、曱苯與二甲苯；醇類，如：甲醇、乙醇、異丙醇，等等。可視需要混合使用選自上列兩種或多種溶劑。反應溫度可視需要依據進行反應之化合物設定。反應溫度通常（但不限於）約-20°C至50°C。該反應通常可進行30分鐘至1〇小時，較佳為1-24 10 小時。式(Γ)化合物（其中X與Z2如上述定義，且Z1為Cl-6 烧基)可依下列方法，分兩步驟進行：步驟F-4中，式(IX)化合物（其中X與z2如上述定義，且Z3為氫或Cy烷基)之製法可由式(VIII)化合物（其 15中X與z2如上述定義）與三(cM烷基）氧代锍鹽（如：三甲基氧代锍碘化物）反應。經濟部智慧財產局員工消費合作社印製該反應可於溶劑中進行，包括例如：醚類，如：乙醚、異丙趟、二号烧與四氫吱喃（thf)及1，2-二甲氧乙烷；脂系烴類，如··正己烷、環己烷；芳香烴類，如： 20苯、甲苯與二甲苯，等等。可視需要混合使用選自上列兩種或多種溶劑。反應溫度可視需要依據進行反應之化合物設定。反應溫度通常（但不限於）約_2〇°c至50°C。該反應通常可進行30分鐘至1〇小時，較佳為1-24 -28- 本紙張尺度適用中國國豕標準(CNS)A4規格（21〇 X 297公爱） 200404052 A7 B7 五、發明說明（27) 小時。步驟F-5中，式(I”)化合物（其中χ與Z2如上述定義，且Z1為Cw烷基)之製法可由式(IX)化合物（其中X與Z2如上述定義，且z3為氫或CK5烷基)與還原劑(如：氫硼化鈉 5 或氫化鋰鋁）反應。該反應可於溶劑中進行，包括例如：醚類，如：乙醚、異丙醚、二啐烷與四氫呋喃（THF)& 甲氧乙烷；脂系烴類，如：正己烷、環己烷；芳香烴類，如：苯、曱苯與二甲苯，等等。可視需要混合使用選自上列兩 10 種或多種溶劑。反應溫度可視需要依據進行反應之化合物設定。反應溫度通常(但不限於）約2(Tc至50°c。該反應通常可進行30分鐘至1〇小時，較佳為1-24 小時。 15 化合物(VI)可自商品取得或可採用已知技術製備。 [方法G]The method for printing compounds of formula (Γ) (where X and Z2 are as defined above) printed by employees of the Intellectual Property Bureau of the Ministry of Economic Affairs is as follows: In step F-1, compounds of formula (VII) (where X and Z2 are as defined above) may be similar Method 10 of the method [A], [B], [C], [D] or [E] for the preparation of a compound of formula (I), using a compound of formula (VI) (where Z2 is as defined above) instead of the compound of formula (11) preparation. In step F-2, a compound of formula (VIII) (wherein X and z2 are as defined above) can be prepared by reacting a compound of formula (VII) (wherein X and Z2 are as defined above) with an acid (eg, hydrochloric acid). 15 The reaction can be carried out in a solvent, including, for example: hydrogenated hydrocarbons, such as: dichloromethane, aerosol, and 1,2-digasethane; ethers, such as: ether, isopropyl ether, dioxane, and tetrahydrofuran (THF) and 1,2-dimethoxyethane; alcohols, such as: methanol 'ethanol; water, and so on. If necessary, two or more solvents selected from the above may be mixed and used. 20 The reaction temperature can be set according to the compound to be reacted. The reaction temperature is usually, but not limited to, about 20 ° C to 100 ° C. (: The reaction can usually be performed for 30 minutes to 10 hours, preferably 1-24 hours. In step F-3, the compound of formula (Γ) (where X and Z2 are as defined above) can be prepared by the compound of formula (VIII) (Where X and Z2 are as defined above) and also -27- _This paper size is based on the specifications of the Chinese Standard (CNS) A4 and published by 0x297) ------ 200404052 A7 B7 V. Description of the invention (26) Original agent (Such as: sodium borohydride or aluminum hydride) reaction. The reaction can be carried out in a solvent, including, for example: ethers, such as: diethyl ether, isopropyl ether, dioxane and tetrahydrofuran (THF), and 1,2-dimethoxyethane; aliphatic hydrocarbons, such as: n-hexane , Cyclohexane; aromatic hydrocarbons, such as: 5 benzene, xylene and xylene; alcohols, such as: methanol, ethanol, isopropanol, and so on. If necessary, two or more solvents selected from the above may be mixed and used. The reaction temperature may be set according to the compound to be reacted as required. The reaction temperature is usually, but not limited to, about -20 ° C to 50 ° C. This reaction can be carried out usually for 30 minutes to 10 hours, preferably 1 to 24 for 10 hours. The compound of formula (Γ) (where X and Z2 are as defined above and Z1 is Cl-6 alkyl) can be performed in two steps according to the following method: In step F-4, the compound of formula (IX) (where X and z2 are as The above definition, and Z3 is hydrogen or Cy alkyl) can be prepared by the compound of formula (VIII) (where X and z2 in 15 are as defined above) and tri (cM alkyl) oxophosphonium salt (such as: trimethyl oxo锍 Iodide) reaction. Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs. The reaction can be performed in solvents, including, for example: ethers, such as: ether, isopropane, No. 2 and tetrahydrofuran (thf) and 1,2-dimethylamine. Oxyethane; aliphatic hydrocarbons, such as n-hexane, cyclohexane; aromatic hydrocarbons, such as: 20 benzene, toluene and xylene, and so on. If necessary, two or more solvents selected from the above may be mixed and used. The reaction temperature may be set according to the compound to be reacted as required. The reaction temperature is usually (but not limited to) about -20 ° C to 50 ° C. The reaction can usually be carried out for 30 minutes to 10 hours, preferably 1-24 -28- This paper size is applicable to China National Standard (CNS) A4 (21 × X 297 public love) 200404052 A7 B7 V. Description of the invention ( 27) hours. In step F-5, the compound of formula (I ”) (where χ and Z2 are as defined above, and Z1 is a Cw alkyl group) can be prepared by a compound of formula (IX) (where X and Z2 are as defined above, and z3 is hydrogen or CK5 alkyl) is reacted with a reducing agent (such as sodium borohydride 5 or lithium aluminum hydride). The reaction can be performed in a solvent, including, for example, ethers such as diethyl ether, isopropyl ether, dioxane, and tetrahydrofuran ( THF) &methoxyethane; aliphatic hydrocarbons, such as: n-hexane, cyclohexane; aromatic hydrocarbons, such as: benzene, xylene and xylene, etc. can be mixed and selected from the above two 10 if necessary Or more solvents. The reaction temperature may be set according to the compound to be reacted. The reaction temperature is usually (but not limited to) about 2 (Tc to 50 ° c.) The reaction can usually be performed for 30 minutes to 10 hours, preferably 1- 24 hours. 15 Compound (VI) is commercially available or can be prepared using known techniques. [Method G]

經濟部智慧財產局員工消費合作社印製Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs

(l-a) -29- 本纸張尺度適用中國國家標準(CNS)A4規格（210x297公爱） 200404052 A7 B7 28 五、發明說明(l-a) -29- This paper size is applicable to China National Standard (CNS) A4 (210x297 public love) 200404052 A7 B7 28 V. Description of the invention

(丨丨-a') Z 類似方法[Α]-[Ε] ’但改用(ΙΙ-a，)替代(Π)(丨丨 -a ') Z Similar method [Α]-[Ε] ’but use (ΙΙ-a,) instead of (Π)

化合物(I)之立體異構型R型(Ι-a)(其中χ、zl與Z2 10 15 經濟部智慧財產局員工消費合作社印製 20 . [B] ^ [C] . [D]4[E]tt^ ^ 化3物之方法，改用式(n_a)化合物（其中2l與z2 定義）替代式(II)化合物製備。、如上玉化合物(I)之立體異構型S型(I-a，)(其中χ、χ1與^ 如上述定義）可類似方法[A]、[B]、[C]、[D]或间中製備: ⑴化合物之方法，改用式(II_a，)化合物（其中zl ^ 述定義）替代式(II)化合物製備。化合物(ΙΙ-a)或(ΙΙ-a’)可採用已知技術製傷。當式⑴所示化合物或其鹽之結構式具有不對稱碳時，其光學活性化合物與消旋混合物亦包括在本發明範圍内。式⑴所示化合物之典型鹽類包括由本發明化合物與；物酸或有機酸，或與有機鹼或無機鹼反應製成之鹽類。e 知此等鹽類分別為酸加成鹽與驗加成鹽。可形成酸加成鹽之酸包括無機酸類，如（但不限於）：硫酸、磷酸、鹽酸、氫溴酸、氫碘酸，等等，及有機龜類，如（但不限於）：對甲苯磺酸、甲磺酸、草酸、對溴戈 -30-本纸張尺度適用中國國家標準(CNS)A4規格（210 X 297公釐） 200404052 A7 B7 五、發明說明（29 磺酸、碳酸、琥珀酸、檸檬酸、笑田^ 本甲酸、乙酸，等等。鹼加成鹽包括彼等衍生自盔施土曰煞機鹼者，如（但氫氧化銨、鹼金屬氫氧化物、鹼於）. 睡、碳酸氫鹽，金屬虱乳化物、碳酸 | 專寺及何生自有機鹼者，如(但不限於）：乙醇胺、三乙胺、參（羥甲A (-不限鹼實例包括：氫氧化鈉、氫氧化鈿寻寺無機乳+ut鉀、碳酸鉀、酸氫納、碳酸氫_、氫氧化約、碳峻舞，等等。反本發明化合物或其鹽依其取代一低破數烧基S旨或已知之其他3旨類，’可經修鋅形成 10 15 經濟部智慧財產局員工消費合作社印製 20 合物。此等S旨類、水合物與溶人3水合物或其他溶内。 °物均包括在本發明範圍本發明化合物可呈π服形式投藥，如（但不限於）：一般錠劑與腸雜包衣㈣、膠囊、丸劑、㈣、粒劑、醜知！酊^ /合液、懸〉于液、糖聚、固態與液態氣霧劑與乳液-亦可呈非經腸式型式投藥，如（但不限於）：經靜脈内腹膜内、皮下、肌内，等等習知製藥技藝之人士熟知之型式。本發明化合物可經由局部使用合適之鼻内用媒劑，呈經鼻式投藥型式，或經由穿皮式途徑，採用習此相關技藝之人士熟知之穿皮式傳送系統投藥。使用本發明化合物之劑量療程係由習此相關技藝之人士依據多種因素選擇，包括（但不限於）：接受者之年齡、體重、性別與醫學病症、所治療病症之嚴重性、投藥途徑、接受者之代謝程度與***功能、所使用之劑量、所使用之特定化合物與其鹽。 -31- 本紙張尺度適用中國國家標準(CNS)A4規格（21〇χ297公釐） A7Stereoisomeric form R (I-a) of compound (I) (where χ, zl, and Z2 10 15 are printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs 20. [B] ^ [C]. [D] 4 [ E] tt ^^ The method of converting 3 compounds is prepared by replacing the compound of formula (II) with a compound of formula (n_a) (wherein 2l and z2 are defined). The stereoisomeric form S (Ia, ) (Where χ, χ1, and ^ are as defined above) can be prepared in a similar manner [A], [B], [C], [D] or occasionally: ⑴ compound method, use the compound of formula (II_a,) (where zl ^), instead of the compound of formula (II). Compound (II-a) or (III-a ') can be prepared by known techniques. When the compound of formula (I) or its salt has an asymmetric carbon In this case, the optically active compounds and racemic mixtures thereof are also included in the scope of the present invention. Typical salts of the compounds represented by formula (2) include those made from the compounds of the present invention; Salts. E Know that these salts are acid addition salts and test addition salts. Acids that can form acid addition salts include inorganic acids such as (but not limited to): sulfuric acid, phosphoric acid Hydrochloric acid, hydrobromic acid, hydroiodic acid, etc., and organic turtles, such as (but not limited to): p-toluenesulfonic acid, methanesulfonic acid, oxalic acid, p-bromo-30 (CNS) A4 specification (210 X 297 mm) 200404052 A7 B7 V. Description of the invention (29 sulfonic acid, carbonic acid, succinic acid, citric acid, Xiaotian ^ formic acid, acetic acid, etc. Alkali addition salts include them Derived from those who wear bases and helmets, such as (but ammonium hydroxide, alkali metal hydroxides, alkalis). Sleep, bicarbonate, metal lice emulsions, carbonic acid | Zhuanji and He Sheng from organic alkali , Such as (but not limited to): ethanolamine, triethylamine, ginseng (hydroxymethyl A (-unlimited alkali examples include: sodium hydroxide, Li Xunsi inorganic milk + ut potassium, potassium carbonate, sodium bicarbonate, carbonic acid Hydrogen, hydrogen hydroxide, carbon dioxide, etc. The compound of the present invention or its salt replaces a low-carbon group S or other known three purposes, and can be modified to form 10 15 Ministry of Economic Affairs Intellectual Property Bureau employees consume cooperatives to print 20 compounds. These S categories, hydrates, and soluble trihydrate or other solvents The compounds are included in the scope of the present invention. The compounds of the present invention can be administered in the form of pi, such as (but not limited to): general lozenges and intestinal miscellaneous coatings, capsules, pills, tinctures, granules, ugly! / Mixed solution, suspension> in liquid, sugar poly, solid and liquid aerosols and emulsions-can also be administered parenterally, such as (but not limited to): intravenous intraperitoneal, subcutaneous, intramuscular, etc. Those who are familiar with pharmaceutical technology. The compounds of the present invention can be administered topically using a suitable intranasal vehicle, in the form of nasal administration, or through the percutaneous route, by those skilled in the art. Drug delivery via a leather delivery system. The dosage course of use of the compound of the present invention is selected by those skilled in the relevant arts based on a variety of factors, including (but not limited to): the recipient's age, weight, gender, and medical condition, the severity of the condition being treated, the route of administration, acceptance Their metabolic degree and excretory function, the dosage used, the specific compounds used and their salts. -31- This paper size is applicable to China National Standard (CNS) A4 specification (21 × 297 mm) A7

經濟部智慧財產局員工消費合作社印製 200404052 本發明化合物最好在投藥前先與一種或多種醫藥上可接文之賦形劑共同調配。賦形劑為惰性物質，如（但不限於）：載劑、稀釋劑、調味劑、甜味劑、潤滑劑、溶解劑、懸浮劑、結合劑、錠劑崩解劑與包埋物質。 5 本發明另一項具體實施例為包含本發明化合物與一種或多種醫藥上可接受之賦形劑之醫藥調配物，該賦形劑應可與調配物中其他成分相容且不傷害其接受者。本發明醫藥調配物之製法為組合醫療有量之本發明化合物與一種或多種醫藥上可接受之賦形劑。製造本發明組合物時，活性 10成分可與稀釋劑混合，或包埋在載劑中，其可呈膠囊、藥包、紙或其他容形式。載劑可作為稀釋劑，其可呈固態、半固態、或液態物質作為媒劑使用，或可呈錠劑、丸劑、散劑、***錠、酏劑、懸浮液、乳液、溶液、糖漿、氣霧劑、油膏（其中包含例如：至高10重量％活性化合 15物）、軟性與硬性明膠囊、栓劑、無菌注射液與無菌包裝散劑。口服用之活性成分可與口服用之無毒性醫藥上可接受之載劑組合，如（但不限於）：乳糖、澱粉、蔗糖、葡萄糖、碳酸鈉、甘露糖醇、山梨糖醇、碳酸鈣、磷酸鈣、硫 20酸鈣、甲基纖維素，等等；可視需要併用崩解劑，如（但不限於）：玉米澱粉、曱基纖維素、洋菜、皂土、黃原膠、藻酸，等等；且可視需要併用結合劑，例如（但不限於）··明膠、天然糖類、泠-乳糖、玉米甜味劑、天然與合成膠、金合歡膠、黃耆膠、藻酸鈉、羧甲基纖維素、聚乙 -32- 本紙張尺度適用中國國家標準(CNS)A4規格（21〇χ297公釐）Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs 200404052 The compound of the present invention is preferably formulated with one or more pharmaceutically acceptable excipients before administration. Excipients are inert substances such as (but not limited to): carriers, diluents, flavoring agents, sweeteners, lubricants, dissolving agents, suspending agents, binding agents, lozenge disintegrating agents, and embedding substances. 5 Another embodiment of the present invention is a pharmaceutical formulation comprising a compound of the present invention and one or more pharmaceutically acceptable excipients, the excipient should be compatible with other ingredients in the formulation without harming its acceptance By. The pharmaceutical formulation of the present invention is prepared by combining a medical amount of the compound of the present invention with one or more pharmaceutically acceptable excipients. When manufacturing the composition of the present invention, the active ingredient 10 may be mixed with a diluent or embedded in a carrier, which may be in the form of a capsule, a sachet, a paper or other contents. Carriers can be used as diluents. They can be used as vehicles in the form of solid, semi-solid, or liquid substances. Aerosols, ointments (including, for example, up to 10% by weight of active compound 15), soft and hard gelatin capsules, suppositories, sterile injection solutions and sterile packaging powders. Active ingredients for oral use can be combined with non-toxic pharmaceutically acceptable carriers for oral use, such as (but not limited to): lactose, starch, sucrose, glucose, sodium carbonate, mannitol, sorbitol, calcium carbonate, Calcium phosphate, calcium sulphate 20, methylcellulose, etc .; disintegrating agents such as (but not limited to) corn starch, amaranth, bentonite, xanthan gum, alginic acid, if necessary , Etc .; and combining agents as needed, such as (but not limited to) ... gelatin, natural sugars, lactose, corn sweetener, natural and synthetic gum, acacia gum, tragacanth gum, sodium alginate, Carboxymethylcellulose, polyethylene-32- This paper size is applicable to China National Standard (CNS) A4 (21 × 297 mm)

200404052 Α7 Β7 五、發明說明（31 二醇、蠟類’等等；且可視需要併用潤滑劑，例如(但不限於）：硬脂酸鎂、硬脂酸鈉、硬脂酸、油酸鈉、苯甲酸鈉、乙酸鈉、氯化鈉、滑石，等等。散劑形式中之載劑可為細碎固體，其與細碎之活性成 5分混合。活性成分可與具有結合性質之载劑，依合適比例混合’並壓縮成所需形狀與大小，產生旋劑。散劑斑疑劑最好包含約丨至約99重量％活性成分，其係新敎本發明組合物。合適之固態載縣緣甲基纖維钱、低溶點壤與可可奶油。 10 無菌液態調配物包括懸浮液、乳液、糖漿與酏劑。活性成分可溶解或懸浮於醫藥上可接受之載劑中，如：無菌水、無菌有機溶劑、或無菌水與無菌有機溶劑兩者之混合物。活性成分亦可溶於合適之有機溶劑中，例如：聚乙一 15醇水溶液。其他組合物可由細碎之活性成分勻散於殺粉或羧甲基纖維素鈉之水溶液中或勻散於合適油中製成。’ 經濟部智慧財產局員工消費合作社印製調配物可呈單一劑型，其係含有單位劑量之物理性分離單位，適合投與人類或其他哺乳動物。單位劑型可為^ 囊或録:劑，或為許多膠囊或錠劑。”單位劑量，，為經計嘗可 20產生所需醫療效果之預定量本發明活性化合物，與一種或多種賦形劑組合。單位劑量中之活性成分量可以在約至約1000毫克或更高用量之間，依所涉及之特定處理而變化或調整。本發明典型之口服劑量當用於指定效果時，其範圍在 ^紙張尺度適用中國國家標準(CNS)A4規格（21〇χ2 -33- 200404052 Α7 Β7 五、發明說明（32 ) 約 O.Olmg /kg/天至約 100 mg/kg/天，以 O.lmg/kg/天至 30 mg/kg/天較佳，以約0.5 mg/kg/天至約10 mg/kg/天最佳。若非經腸式投藥時，已證實，一般有利之投藥量為約 0.001 至 100mg/kg/天，以〇.〇lmg/kg/天至 lmg/kg/天較 5 佳。本發明化合物可呈單一每日劑量投藥，或每日總劑量可分成小劑量，每天投藥2、3次或更多次。若呈穿皮式投藥型式時，當然為連續性投藥。實例 10 本發明將以實例之型式說明，但此等實例並無意構成本發明之界定範圍。下列實例中，所有定量數據除非另有說明，否則係指重量百分比。經濟部智慧財產局員工消費合作社印製質譜係採用電喷麗（ES)離子化技術（Micromass 15 Platform LC)取得。熔點未經校正。液相層析法-質譜(LC-MS)數據係於加裝 shimadzu Phenomenex ODS 管柱(4.6 mm 0 X 30 mm)之 Micromass Platform LC，以乙腈-水(9:1 至 1:9) ’依lml/分鐘之流速溶離後取得。TLC係於預先塗覆好之矽膠板上(Merck矽膠60 F-254)上進行。所有管柱層 20 析分離法均使用矽膠(WAKO-凝膠C-200(75-150 μιη))。所有化學藥品均為試劑級，且購自Sigma-Aldrich藥廠、200404052 Α7 Β7 V. Description of the invention (31 diols, waxes, etc.); and lubricants can be used as needed, such as (but not limited to): magnesium stearate, sodium stearate, stearic acid, sodium oleate, Sodium benzoate, sodium acetate, sodium chloride, talc, etc. The carrier in the powder form can be a finely divided solid, which is mixed with the finely divided active to 5 points. The active ingredient can be combined with a carrier with binding properties, in an appropriate proportion Mixing and compressing to the desired shape and size to produce a spin agent. The powder spotting agent preferably contains about 丨 to about 99% by weight of the active ingredient, which is the composition of the present invention. A suitable solid-state fiber Money, low melting point soil and cocoa butter. 10 Sterile liquid formulations include suspensions, emulsions, syrups and elixirs. The active ingredients can be dissolved or suspended in pharmaceutically acceptable carriers such as sterile water, sterile organic solvents Or a mixture of sterile water and a sterile organic solvent. The active ingredient can also be dissolved in a suitable organic solvent, such as an aqueous solution of polyethylene glycol 15. Other compositions can be dispersed in finely divided active powder by finely divided active ingredients. Carboxymethylcellulose sodium aqueous solution or evenly dispersed in suitable oils. 'The formulation printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economy can be in a single dosage form, which is a physical separation unit containing a unit dose, suitable for investment With humans or other mammals. The unit dosage form can be a capsule or capsule, or a number of capsules or lozenges. "A unit dose is a predetermined amount of the active compound of the present invention that can produce the desired medical effect over 20%, In combination with one or more excipients. The amount of active ingredient in a unit dose can be between about and about 1000 milligrams or more, depending on the particular treatment involved. Typical oral doses of the present invention are used when When the effect is specified, its range is ^ paper scale. Applicable to China National Standard (CNS) A4 specification (21〇χ2-33- 200404052 Α7 Β7) V. Description of the invention (32) About 0.01 mg / kg / day to about 100 mg / kg / Day, preferably from 0.1 mg / kg / day to 30 mg / kg / day, and most preferably from about 0.5 mg / kg / day to about 10 mg / kg / day. If parenteral administration has been confirmed, A generally advantageous dosage is about 0.001 to 100 mg / kg / day, with 0.001 mg / kg / day to 1 mg / kg / day is better than 5. The compound of the present invention can be administered in a single daily dose, or the total daily dose can be divided into small doses, which are administered 2, 3 or more times per day. In the case of transdermal administration, it is of course continuous administration. Example 10 The present invention will be described by way of examples, but these examples are not intended to define the scope of the present invention. In the following examples, all quantitative data are provided unless otherwise specified Otherwise, it refers to the weight percentage. The mass spectrometry printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs was obtained using Electrospray (ES) ionization technology (Micromass 15 Platform LC). Melting points are uncorrected. Liquid chromatography-mass spectrometry (LC-MS) data was obtained on a Micromass Platform LC with Shimadzu Phenomenex ODS columns (4.6 mm 0 X 30 mm). Acetonitrile-water (9: 1 to 1: 9) was used. Obtained after dissolution at a flow rate of 1 ml / min. TLC is performed on a pre-coated silicone board (Merck Silicone 60 F-254). Silica gel (WAKO-Gel C-200 (75-150 μm)) was used for all column separations. All chemicals are reagent grade and purchased from Sigma-Aldrich Pharmaceuticals,

Wako pure chemical Industries，Ltd·藥廠、Tokyo kasei kogyo co. Ltd·藥廠、Arch corporation 藥薇。所有起始物均可自商品取得或可使用文獻上所述方法 -34- 本纸張尺度適用中國國家標準(CNS)A4規格（21〇χ297公釐） 200404052 A7 B7 五、發明說明（33) 製備。本發明化合物之效果可採用下列分析法及藥物試驗檢驗。 5 [於人類之VR1-轉感染CHO細胞株中測定辣椒素誘發之 Ca2+流入量](分析法1) (1) 建立人類VR1 -CHO luc9aeq細胞株經濟部智慧財產局員工消費合作社印製自切除神經軸之背根神經節集合庫中選殖出人類類香草受體（hVRl)cDNA(WO 00/29577)。選殖出之 hVRl 10 cDNA使用pcDNA3載體構築，轉感染至CH01uc9aeq細胞株中。該細胞株含有多管水母素(aequorin)與CRE-勞光素酶報導子基因作為讀取訊號。採用限制稀釋法，於選拔培養基（補充10% FCS、1.4mM丙酮酸納、20 mM HEPES、0.15%碳酸氫鈉、100 U/ml 青黴素、lOOpg/ml 鏈 15 黴素、2 mM麵醯胺、非必需胺基酸與2 mg/ml G418之 DMEM/F12培養基(Gibco BRL))中選殖出轉感染體。於受辣椒素刺激之純系中檢驗Ca2+流入量。選出高反應性之純系，進一步用於計晝實驗。人類VRl-CH01uc9aeq細胞保持在選拔培養基中，每3-4天，依1-2·5χ105個細胞/燒 20 瓶(75 mm2)傳代一次。 (2) 使用FDSS-3000測定Ca2+流入量取人類VR1-CHO luc9aeq細胞懸浮於與選拔培養基相同之培養基中，但其中不含G418，以每孔1〇〇〇個細胞之接種密度接種至384孔分析板中（黑色隔間透明底座/ -35-Wako pure chemical Industries, Ltd. Pharmaceutical Factory, Tokyo kasei kogyo co. Ltd. Pharmaceutical Factory, Arch corporation Yaowei. All starting materials can be obtained from the commodity or the method described in the literature can be used. -34- This paper size applies to the Chinese National Standard (CNS) A4 specification (21 × 297 mm) 200404052 A7 B7 V. Description of the invention (33) preparation. The effects of the compounds of the present invention can be tested by the following analytical methods and pharmaceutical tests. 5 [Determination of capsaicin-induced Ca2 + influx in human VR1-transfected CHO cell line] (Analytical Method 1) (1) Establishment of human VR1 -CHO luc9aeq cell line, Consumer Cooperative of Intellectual Property Bureau, Ministry of Economic Affairs, printed self-excision A human vanilla receptor (hVR1) cDNA was selected from the dorsal root ganglion ganglia of the nerve axis (WO 00/29577). The selected hVRl 10 cDNA was constructed using the pcDNA3 vector and transfected into the CH01uc9aeq cell line. This cell line contains aequorin and a CRE-Laurinase reporter gene as read signals. The limiting dilution method was used in the selection medium (supplemented with 10% FCS, 1.4 mM sodium pyruvate, 20 mM HEPES, 0.15% sodium bicarbonate, 100 U / ml penicillin, 100 pg / ml streptomycin, 2 mM melanthamine, Transfectants were selected from non-essential amino acids and 2 mg / ml G418 in DMEM / F12 medium (Gibco BRL). Ca2 + influx was examined in pure lines stimulated by capsaicin. The pure lines with high reactivity were selected for further day-to-day experiments. Human VRl-CH01uc9aeq cells were kept in the selection medium and passaged every 3-4 days at 1-2 · 5x105 cells / burnt in 20 bottles (75 mm2). (2) Calculate the influx of Ca2 + using FDSS-3000. Take human VR1-CHO luc9aeq cells and suspend them in the same medium as the selection medium, but not G418. Analysis board (black compartment with transparent base / -35-

200404052 A7 B7 五、發明說明（34 )200404052 A7 B7 V. Description of the invention (34)

Nalge Nunc International) 〇培養48小時後，培養基換成含 2 μΜ Fluo-3 AM (Molecular Probes)與 0.02% Puronic F-127之分析緩衝液（漢氏(Hank’s)平衡鹽溶液(HBSS)、17 mM HEPES (ρΗ7·4)、1 mM 羧苯磺丙胺、o.i% BSA)，細 5胞於25°C下培養60分鐘。以分析緩衝液洗滌2次後，細胞與試驗化合物或媒劑於25°C下培養20分鐘。以10 nM 辣椒素刺激60秒後，採用FDSS-3000測定細胞質中Ca2+ 之移動篁(λ ex=488nm ’ λ em=540nm / Hamamatsu Photonics)。計算積分之R值，與對照組比較。 10 [於一級培養之大老鼠背根神經節神經元中測定辣椒素誘發之Ca2+流入量](分析法2) (1)背根神經節神經元之製法殺死新生之Wister大老鼠(5-11天大），取出背根神經 15 節（DRG)。使 DRG 與 0.1%胰蛋白酶(GibcoBRL)於 PBS(_ )(Gibco BRL)中，在37。(：下培養30分鐘後，添加一半體積之胎牛血清(FCS)，離心分離細胞。DRG神經元細胞再懸浮於Ham F12/5% FCS/5%馬血清(Gibco BRL)中，採用重覆吸取法勻散’通過70 μιη筛網(Falcon)。 20 培養板於37°C下培養3小時，以排除污染之Schwann 細胞。回收未附著之細胞，再於塗覆昆布胺酸之384孔分析板（Nunc)中培養，1χΐ〇4個細胞/5〇 μΐ/孔，於50 ng/ml 重組體大老鼠NGF(Sigma)與50 μΜ 5-氟去氧尿嘧啶核苷 (Sigma)之存在下培養2天。言绩經濟部智慧財產局員工消費合作、社印製 -36-Nalge Nunc International) After 48 hours of incubation, the medium was changed to an analysis buffer (Hank's balanced salt solution (HBSS), 17 mM) containing 2 μM Fluo-3 AM (Molecular Probes) and 0.02% Puronic F-127. HEPES (ρΗ7.4), 1 mM sulfamethoxamine, oi% BSA), 5 cells were cultured at 25 ° C for 60 minutes. After washing twice with analysis buffer, the cells were incubated with the test compound or vehicle at 25 ° C for 20 minutes. After stimulating with 10 nM capsaicin for 60 seconds, FDSS-3000 was used to measure the movement of Ca2 + in the cytoplasm (λ ex = 488nm ′ λ em = 540nm / Hamamatsu Photonics). The R value of the integral is calculated and compared with the control group. 10 [Determination of capsaicin-induced Ca2 + influx in dorsal root ganglion neurons of primary cultured rats] (Analytical Method 2) (1) The method of making dorsal root ganglion neurons kills newborn Wister rats (5- 11 days old), and 15 DRGs were removed. Make DRG with 0.1% trypsin (GibcoBRL) in PBS (_) (Gibco BRL) at 37. (: After 30 minutes of incubation, add half the volume of fetal calf serum (FCS) and centrifuge the cells. DRG neuron cells were resuspended in Ham F12 / 5% FCS / 5% horse serum (Gibco BRL) and repeated. Disperse by pipetting through a 70 μm sieve (Falcon). 20 Incubate the plate at 37 ° C for 3 hours to exclude contaminated Schwann cells. Recover unattached cells and analyze in 384 wells coated with kubumic acid Cultured in a plate (Nunc), 1 × 104 cells / 50 μΐ / well in the presence of 50 ng / ml recombinant rat NGF (Sigma) and 50 μM 5-fluorodeoxyuracil riboside (Sigma) Cultivate for 2 days. Words: Intellectual Property Bureau, Ministry of Economic Affairs, Consumer Co-operation, Social Printing -36-

200404052 A7 B7 五、發明說明（35) (2)Ca2+移動性分析法以補充 17 mM HEPES(pH 7.4)與 0.1% BSA 之 HBSS 洗條DRG神經元細胞兩次。與2 μΜ fluo-3AM(Molecular Probe)、0.02% PF127 (Gibco BRL)與 ImM 羧苯磺丙胺 5 (Sigma)於37°C下培養40分鐘，洗滌細胞3次。細胞與 VR1擷抗劑或媒劑（二曱亞砜)培養後，與ΐμΜ辣椒素於 FDSS-6000 中培養（λ ex=480nm， λ em=520nm / Hamamatsu Photonics)。於 480nm 下追蹤螢光變化 2.5 分鐘。計算積分之R值，與對照組比較。 10 [測定辣椒素誘發之膀胱收縮之器官浴分析法](分析法3) 取雄性Wistar大老鼠（10週大)接受醚麻醉後，以斷頭法殺死。取出整個膀胱，置入充入氧氣之改良式Krebs_200404052 A7 B7 V. Description of the invention (35) (2) Ca2 + mobility analysis method Twisted DRG neuron cells supplemented with HBSS 17 mM HEPES (pH 7.4) and 0.1% BSA. The cells were washed with 2 μM fluo-3AM (Molecular Probe), 0.02% PF127 (Gibco BRL), and 1 mM sulfamethoxamine 5 (Sigma) for 40 minutes at 37 ° C, and the cells were washed 3 times. After the cells were cultured with VR1 anti-adjuvant or vehicle (disulfoxide), they were cultured with ΐμΜ capsaicin in FDSS-6000 (λ ex = 480nm, λ em = 520nm / Hamamatsu Photonics). Track fluorescence changes at 480nm for 2.5 minutes. The R value of the integral is calculated and compared with the control group. 10 [Analysis of organ bath for measuring capsaicin-induced bladder contraction] (Analytical Method 3) Male Wistar rats (10 weeks old) were anesthetized with ether and killed by decapitation. Take out the entire bladder and insert the modified Krebs_

Henseleit 溶液（pH 7.4)中（其組成如下：112 mMNaC卜 5·9 15 mM KC1、1.2 mM MgCl2、1.2 mM NaH2P〇4、2 mM CaCl2、2.5 mM NaHC03、12 mM葡萄糖）。依過去文獻戶斤述研究收縮反應[Maggi CA et al: Br.J.Pharmacol· 108:801- 經濟部智慧財產局員工消費合作社印製 805，1993]。於1克承載量下，使用大老鼠迫肌縱向長條記錄等距張力。每次刺激前，膀胱長條先平衡6〇分鐘。 20 每15分鐘間隔測定其對80 mM KC1之收縮反應，直到得到再現性之結果為止。採用對KC1之反應作為内標準，以評估其對辣椒素之最大反應。由迫肌長條先與化合物培養 3〇分鐘後，再接受ΙμΜ辣椒素(媒劑：80%生理食鹽水、 100/〇EtOH與10% Tween 80)刺激培養30分鐘，探討化合 -37- 本紙張尺度適用中國國家標準(CNS)A4規格（210x297公釐） A7 B7Henseleit solution (pH 7.4) (its composition is as follows: 112 mM NaC, 5.9 15 mM KC1, 1.2 mM MgCl2, 1.2 mM NaH2P04, 2 mM CaCl2, 2.5 mM NaHC03, 12 mM glucose). The contraction response was studied according to the previous literature [Maggi CA et al: Br.J. Pharmacol. 108: 801- Printed by the Consumer Consumption Cooperative of the Intellectual Property Bureau of the Ministry of Economy 805, 1993]. At a load of 1 gram, the isometric tension was recorded using longitudinal strips of the rat muscle. Before each stimulation, the bladder strips were equilibrated for 60 minutes. 20 The contractile response to 80 mM KC1 was measured at 15-minute intervals until reproducible results were obtained. The response to KC1 was used as an internal standard to assess its maximum response to capsaicin. The muscle strip was cultured for 30 minutes with the compound, and then stimulated with 30 μm of capsaicin (vehicle: 80% physiological saline, 100 / 〇EtOH and 10% Tween 80) for 30 minutes. Paper size applies to China National Standard (CNS) A4 (210x297 mm) A7 B7

經濟部智慧財產局員工消費合作社印製 200404052 物之效應。取同一隻動物製作之檢體作為對照組，其餘則用於分析化合物。分別計算辣椒素誘發之收縮量與内標準 (亦即KC1誘發之收縮量）之比例，分析試驗化合物對辣椒素誘發收縮之效果。 5 [於人類P2X1轉感染之CHO細胞株中測定Ca2+流入量] (1) 人類P2X1轉感染CH01uc9aeq細胞株之製法建立人類P2X1轉感染之CH01uc9aeq細胞株，保持Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs 200404052. Specimens made from the same animal were used as control groups, and the rest were used for compound analysis. The ratio of capsaicin-induced contraction to the internal standard (that is, KC1-induced contraction) was calculated separately, and the effect of the test compound on capsaicin-induced contraction was analyzed. 5 [Determination of Ca2 + influx in human P2X1 transfected CHO cell line] (1) Method for preparing human P2X1 transfected CH01uc9aeq cell line Establish human P2X1 transfected CH01uc9aeq cell line and maintain

在補充 7.5% FCS、20 mM HEPES-KOH (pH 7.4)、1.4mM 10 丙酮酸鈉、100 U/ml青黴素、lOOpg/mi鏈黴素、2 mM麵醯胺(Gibco BRL)與0.5 U/ml腺苷三磷酸雙磷酸(第I級， Sigma藥廠)之杜氏改良伊格氏培養基(Dulbecco，s modified Eagle*s medium)(DMEM/F 12)中。取懸浮之細胞接種至 384-孔透明底板之黑色分析板中（Nalge Nunc 15 International)，3 xlO3 / 50 μΐ/孔。細胞繼續培養 48 小時，使細胞附著在分析板上。 (2) 細胞内Ca2+濃度之測定使用登光 Ca 螯合染料 Fluo-3 AM (Molecular Probes) 測定胞液中Ca2+濃度因P2X1受體促效劑所媒介之增加 20 量。以洗務缓衝液(HBSS，17 mM HEPES-KOH(pH 7.4)、 0.1% BSA與0·5單位/ml腺苷三磷酸雙磷酸)洗滌附著在分析板上之細胞2次，於40 μΐ承載緩衝液(含1 μΜ Fluo-3 AM、ImM 羧苯磺丙胺、ΙμΜ 環孢素 a、0.01% pluronic (Molecular Probes)之洗滌缓衝液）中，於暗處下培養1小 -38- 本纸張尺度適用中國國家標準(CNS)A4規格（210x297公釐）After supplementation with 7.5% FCS, 20 mM HEPES-KOH (pH 7.4), 1.4 mM 10 sodium pyruvate, 100 U / ml penicillin, 100 pg / mi streptomycin, 2 mM methamidine (Gibco BRL), and 0.5 U / ml Adenosine triphosphate bisphosphate (level I, Sigma Pharmaceuticals) in Dulbecco's modified Eagle's medium (DMEM / F 12). The suspended cells were seeded into a 384-well transparent bottom plate in a black assay plate (Nalge Nunc 15 International), 3 x 10/50 μΐ / well. The cells were cultured for another 48 hours, allowing the cells to attach to the assay plate. (2) Measurement of intracellular Ca2 + concentration The Dengguang Ca chelating dye Fluo-3 AM (Molecular Probes) was used to measure the Ca2 + concentration in the cytosol due to the increase in the amount of P2X1 receptor agonist by 20. Wash cells attached to the assay plate twice with wash buffer (HBSS, 17 mM HEPES-KOH (pH 7.4), 0.1% BSA, and 0.5 units / ml adenosine triphosphate bisphosphate), and load at 40 μΐ Buffer (containing 1 μM Fluo-3 AM, ImM Carbsulfenylamine, 1 μM Cyclosporin a, 0.01% pluronic (Molecular Probes) washing buffer), culture 1-38 in the dark Standards apply to China National Standard (CNS) A4 (210x297 mm)

200404052 Α7 Β7 五、發明說明（37 ) 時。以40μ1洗條緩衝液洗滌分析板2次’在各孔中添加 35 μΐ洗滌緩衝液與5 μΐ試驗化合物或作為標準物之 2，，3，-鄰-(2,4,6-三硝基苯基）腺苷5’-三磷酸（Molecular Probes)。進一步於黑暗中培養1〇分鐘後’添加200 nM 5 α，θ-亞曱基ATP促效劑，使Ca2+開始移動。依250毫秒之間隔，以FDSS-6000測定螢光強度（Aex=41〇nm，入 em=510nm / Hamamatsu Photonics)。由數據計算積分比例，並與對照組比較。 10 [以麻醉之大老鼠測定辣椒素誘發之膀胱收縮](分析法4) (1) 動物採用雌性Sprague-Dawley大老鼠（200-250 g /日本 Charles River 公司）。 (2) ***導管 15 使大老鼠經腹膜内投與尿烷(Sigma)1.2 g/kg而麻醉。自腹部中線切開，將聚乙烯導管（BECTON DICKINSON， PE50)經過膀胱圓頂***。依平行方向切開腹股溝區，將經濟部智慧財產局員工消費合作社印製填充含 2 IU/ml 肝素(Novo Heparin，Aventis Pharma)之生理食鹽水(Otsuka)之聚乙烯導管(Hibiki，規格5)***大股 20 動脈中。 (3) 膀胱内壓測定使膀胱導管經由T形管連接壓力轉換器（vigg0_200404052 Α7 Β7 5. When the invention was explained (37). Wash the assay plate twice with 40 μ1 strip washing buffer. Add 35 μΐ of wash buffer and 5 μΐ of test compound or 2, 3, -o- (2,4,6-trinitro) to each well. Phenyl) adenosine 5'-triphosphate (Molecular Probes). After further incubation in the dark for 10 minutes, 200 nM 5 α, θ-fluorenyl ATP agonist was added, and Ca2 + began to move. Fluorescence intensity was measured at 250 millisecond intervals using FDSS-6000 (Aex = 41.0 nm, em = 510 nm / Hamamatsu Photonics). Calculate the integral ratio from the data and compare it with the control group. 10 [Capsaicin-induced bladder contraction in anesthetized rats] (Analytical Method 4) (1) Animals Female Sprague-Dawley rats (200-250 g / Charles River, Japan) were used. (2) Insert the catheter 15 to anaesthetize rats by intraperitoneally administering 1.2 g / kg of urethane (Sigma). Incision was made from the midline of the abdomen, and a polyethylene catheter (BECTON DICKINSON, PE50) was inserted through the bladder dome. The groin area was cut in parallel, and a polyethylene catheter (Hibiki, size 5) printed with physiological saline (Otsuka) containing 2 IU / ml heparin (Novo Heparin, Aventis Pharma) was inserted and inserted into the groin area of the Ministry of Economic Affairs ’Intellectual Property Bureau. Large femoral artery. (3) Measurement of intravesical pressure Connect the bladder catheter to a pressure transducer via a T-shaped tube (vigg0_

Spectramed Pte Ltd，DT-XXAD)與微注射幫浦(TERUMO)。於室溫下，以2.4ml/小時之速度注入生理食鹽水至膀胱 -39- 本纸張尺度適用中國國家標準(CNS)A4規格（21〇χ297公釐） 200404052 A7Spectramed Pte Ltd (DT-XXAD) and Microinjection Pump (TERUMO). Inject physiological saline into the bladder at a rate of 2.4ml / hour at room temperature -39- This paper size is in accordance with the Chinese National Standard (CNS) A4 specification (21 × 297 mm) 200404052 A7

五、發明說明（π 中。於繪圖記錄器（Yokogawa)上連續記錄膀胱内壓力。在投與試驗化合物之前至少進行3次具再現性之排尿循環，相當於為時20分鐘，並用為底線值。 (4)投與試驗化合物及使用辣椒素刺激膀胱 5 投與化合物之前即停止輸入生理食鹽水。取試驗化合物〉谷於含乙酵、Tween 80 (ICN Biome Inc·)與生理食gg水 (1 : 1 ·· 8，v/v/v)之混合物中，經動脈内投與i〇mg/kg。投與化合物後2分鐘，經動脈内投與溶於乙醇中之1〇/zg 辣椒素(Nacalai Tesque) 〇 10 (5)膀胱内壓參數分析由膀胱内壓數據分析辣椒素誘發膀胱内壓力之相對升高值。由辣椒素誘發之膀胱壓力與沒有辣椒素刺激下之排尿期間最大膀胱壓力比較。採用Student氏t-試驗分析試驗化合物所媒介抑制膀胱壓力升高之效果。低於5%之概 15 率水準則接受為顯著差異。 [於罹患膀胱炎之已麻醉大老鼠中測定膀胱過度活性](分析法5) 經濟部智慧財產局員工消費合作社印製 (1) 動物 20 採用雌性Sprague-Dawley大老鼠（180_250g /日本V. Description of the invention (π). Continuously record the bladder pressure on a chart recorder (Yokogawa). Perform a reproducible urination cycle at least 3 times before the test compound is administered, which is equivalent to 20 minutes, and used as the bottom line value (4) Administration of test compounds and stimulation of the bladder with capsaicin 5 Stop input of physiological saline before administration of compounds. Take test compound> Gu Yu containing acetic acid, Tween 80 (ICN Biome Inc ·) and physiological food gg water ( 1: 1 ·· 8, v / v / v) mixture, intra-arterial administration of 10 mg / kg. 2 minutes after compound administration, intra-arterial administration of 10 / zg pepper dissolved in ethanol Nacalai Tesque 〇10 (5) Analysis of bladder pressure parameters Based on the bladder pressure data, the relative increase in the pressure of bladder induced by capsaicin is analyzed. The bladder pressure induced by capsaicin is the largest during urination without capsaicin stimulation. Bladder pressure comparison. Student's t-test was used to analyze the effect of the test compound in inhibiting the increase in bladder pressure. A probability of less than 5% was accepted as a significant difference in water criterion. [Measured in anaesthetized rats with cystitis bladder Overactivity] (Analysis 5) Ministry of Economic Affairs Intellectual Property Office employees consumer cooperatives print (1) the use of animal 20 female Sprague-Dawley rats large (180_250g / Japan

Charles River公司）。實驗前48小時，取溶於生理食鹽水中之環磷醯胺(CYP)，經腹膜内投與150mg/kg。 (2) ***導管使大老鼠經腹膜内投與尿烧(Sigma)1.25 g/kg而麻醉。 -40- 本紙張尺度適用中國國家標準(CNS)A4規格（210 X 297公釐） 200404052 A7 B7 五、發明說明（39) 自腹部中線切開，將聚乙烯導管（BECTON DICKINSON， PE50)經過膀胱圓頂***。依平行方向切開腹股溝區，將填充生理食鹽水（Otsuka)之聚乙烯導管（BECTON DICKINSON，PE50)***股靜脈中。待膀胱排空後，使大 5 老鼠靜置1小時，以便自手術中恢復。 (3) 膀胱内壓測定使膀胱導管經由T形管連接壓力轉換器（Vigg〇-Charles River). 48 hours before the experiment, cyclophosphamide (CYP) dissolved in physiological saline was taken and administered 150 mg / kg intraperitoneally. (2) Catheterization The rats were anesthetized by intraperitoneal administration of 1.25 g / kg of urinary fever (Sigma). -40- This paper size is in accordance with Chinese National Standard (CNS) A4 (210 X 297 mm) 200404052 A7 B7 V. Description of the invention (39) Incision from the midline of the abdomen, a polyethylene catheter (BECTON DICKINSON, PE50) is passed through the bladder Dome inserted. The groin area was cut in parallel, and a polyethylene catheter (BECTON DICKINSON, PE50) filled with physiological saline (Otsuka) was inserted into the femoral vein. After the bladder is emptied, 5 rats are allowed to stand for 1 hour to recover from the surgery. (3) Measurement of intravesical pressure Connect the bladder catheter to a pressure transducer (Vigg〇-

Spectramed Pte Ltd，DT-XXAD)與微注射幫浦（TERUM〇）。於室溫下，以3.6ml/小時之速度注入生理食鹽水至膀胱中 10 20分鐘。於繪圖記錄器（Y〇k〇gawa)上連續記錄膀胱内壓力。在投與試驗化合物之前至少進行3次具再現性之排尿循壞’相當於為時20分鐘。 (4) 投與試驗化合物取试驗化合物溶於含乙醇、Tween 80 (ICN Biome dml I5 Inc·)與生理食鹽水（1 : 1 : 8，v/v/v)之混合物中，經靜脈内投與0.05mg/kg、0.5mg/kg或5mg/kg。投與化合物後3分鐘，於室溫下，以3.6ml/小時之速度輸入生理食鹽水 (Nacalai Tesque)至膀胱中。經濟部智慧財產局員工消費合作技印製 (5) 膀胱内壓參數分析 20 依過去曾說明之方法分析膀胱内壓參數[Lecci A et al:Spectramed Pte Ltd (DT-XXAD) and microinjection pump (TERUM). At room temperature, physiological saline was injected into the bladder at a rate of 3.6 ml / hour for 10 to 20 minutes. The intravesical pressure was continuously recorded on a chart recorder (Yokogawa). Reproducible urination at least 3 times before administration of the test compound is equivalent to 20 minutes. (4) Administration of the test compound: The test compound is dissolved in a mixture containing ethanol, Tween 80 (ICN Biome dml I5 Inc ·) and physiological saline (1: 1: 8, v / v / v), intravenously. It was administered at 0.05 mg / kg, 0.5 mg / kg or 5 mg / kg. Three minutes after the administration of the compound, physiological saline (Nacalai Tesque) was input into the bladder at a rate of 3.6 ml / hour at room temperature. Printed by employees of the Intellectual Property Bureau of the Ministry of Economic Affairs on consumer cooperation technology (5) Analysis of bladder pressure parameters 20 Analysis of bladder pressure parameters according to the method described in the past [Lecci A et al:

EurJ· PharmacoL 259: 129_135, 1994]。由膀胱内壓數據分析以排尿間隔時間計算之排尿頻率及以輪入生理食鹽水至第一次排尿時之體積計算之膀胱容量。採用不4^對之 Student氏t_試驗分析試驗化合物所媒介抑制排尿頻 -41- ^本紙張尺度適用中國國家標準(CNS)A4規格（210 X 297公釐） 10 Α7 Β7 驗化合物所媒介增加膀準則接受為顯著差異。所分析里=果。低於敎概率水均值土 SEM。 ‘據為4-7隻大老鼠之平 [急性疼痛之測定] 採用ΪΓ加大老鼠於加熱板上進行。表面m 56^ _4將動物置於加熱板表面(52·56〇，測量動物出現或_)之時間長短。另—種 :二為：(：.細步將試驗動物置於中等溫度之表上’、呵 '、、、板，皿度’並 = 聊為止。當動物開始_ 日守之/JZL度即作為疼痛閥值之測量點。 >由化合物相對於媒劑處理對照組進行試驗。疼痛試驗別，在不同時間點，經由不同投藥途徑心,、I '皮内、穿皮式）投與藥物。 15 i.t.、i.c.v·、s.c. ι_ρ·、ρ.ο· 經濟部智慧財產局員工消費合作社印製 20 [持續性疼痛之測定] 持續性疼痛主要制大錢，以福騎或辣椒素試驗。在試驗動物之-隻後腳上注射1-5%福馬林或ι〇_ _g辣《。待接受福馬林或辣椒素投藥之動物出現感受傷害反應後，如：處理之腳退縮、被频*心在至長卯分鐘之時間範圍内出現感受傷害反應次數即作為疼痛強度測定值。由化合物相對於媒劑處理對照組進行試驗。投與福馬 -42-EurJ. PharmacoL 259: 129_135, 1994]. From the bladder pressure data analysis, the frequency of urination calculated from the interval between urination and the volume of the bladder calculated from the volume of physiological saline in turn to the time of the first urination. The Student's t-test was used to analyze the frequency of urinary inhibition by the test compound -41- ^ This paper size applies the Chinese National Standard (CNS) A4 specification (210 X 297 mm). 10 Α7 Β7 Increase in the test compound media The accepted criteria are significant differences. In the analysis = fruit. Probability below 水 water mean soil SEM. ‘According to 4-7 rats [Determination of acute pain] Use 进行 Γ to increase the mice on a hot plate. The surface m 56 ^ _4 places the animal on the surface of the heating plate (52 · 56 °, and measures the length of time that the animal appears or _). The other kind: two: (:. Place the test animal in a moderate step on a table with a temperature of ',', ',,,,,,, and, and' and = 'until the chat. When the animal begins _ Rishou / JZL degree is regarded as Measurement points of pain threshold. &Gt; The test was performed by the compound relative to the vehicle-treated control group. For the pain test, the drug was administered at different time points through different routes of administration (intradermal, transdermal). 15 i.t., i.c.v ·, s.c. ι_ρ ·, ρ.ο · Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs 20 [Measurement of persistent pain] Continuous pain is mainly made up of large sums of money, which is tested by blessing or capsaicin. Test animals were injected with only 1-5% of formalin or ιο__g. After the animals receiving formalin or capsaicin have experienced a nociceptive response, such as the withdrawal of the treated feet and the frequency of nociceptive reactions within a time span of up to 卯 minutes, it is used as the measurement of pain intensity. Experiments were performed with compounds versus vehicle-treated control groups. Administer Foma -42-

200404052 A7 B7 發明說明（4!) 林或辣椒素之前’在不同時間點，經由不同投藥途經 (i.v·、i.p·、ρ·ο·、i.t.、ix_v·、SX.、皮内、穿皮式）投與藥物。 5 [神經病變性疼痛測定法] 主要於大老鼠中，採用不同方式之單側坐骨神經傷害誘發神經病變性疼痛。該手術係於麻醉下進行。第_種坐骨神經傷害係由共同坐骨神經周圍放置鬆弛之收縮性缚、線產生(Bennett and Xie，Pain 33 (1988):87-107)。第二種方式 10 為緊結紮共同坐骨神經之約一半直徑(Seltzer et 的 % 經濟部智慧財產局員工消費合作社印製 (1990)·· 205- 218)。另一種方法中，採用一組模式，其中在 L5與L6脊柱神經，或只在L5脊柱神經拉緊結紮或橫截 (KIM SH ； CHUNG JM? AN EXPERIMENTAL-MODEL FOR PERIPHERAL NEUROPATHY PRODUCED BY 15 SEGMENTAL SPINAL NERVE LIGATION IN THE RA， PAIN 50 (3) (1992): 355-363)。第四種方式涉及切除坐骨神經三個末端分支中之二個（脛骨與共同腓骨神經）之神經軸，留下完整之腓腸神經，最後一種方式則為僅切除脛骨分支神經，留下腓腸與共同神經未受傷害。對照組動物則 20 接受假手術處理。手術後，神經受損之動物發展出慢性機械性痛覺異常、冷痛覺異常及熱痛覺過敏。機械性痛覺異常係利用壓力轉換器測定（美國 Electronic von Frey Anesthesiometer， IITC Inc.-Life Science Instruments，Woodland Hills, -43- 本紙張尺度適用中國國家標準(CNS)A4規格（210x297公釐） 200404052 Μ Β7 五、發明說明（42 ) SA，USA ;瑞典 Electronic von Frey System，Somedic Sales AB，Horby，Sweden) 〇熱痛覺過敏係採用輻射熱源（腳底試驗：義大利Ugo Basile，Comerio，Italy)測定或利用5-10°C之冷板測定，其 5 中計算受影響之後腳之護傷反應，作為疼痛強度之測定值。另一項冷誘發疼痛之試驗為計算護傷反應之次數，或在受影響之後腳底投與丙酮後測量出現護傷反應之時間長短。慢性疼痛通常記錄其活動力生理時鐘規律（德國200404052 A7 B7 Description of the invention (4!) Before Lin or capsaicin, at different points in time, via different routes of administration (iv ·, ip ·, ρ · ο ·, it, ix_v ·, SX., Intradermal, transdermal ) Administer drugs. 5 [Neuropathic pain assay] In rats, neuropathic pain is induced by unilateral sciatic nerve injury in different ways. The operation is performed under anesthesia. The first type of sciatic nerve injury is caused by the placement of loose contractile tethers and threads around the common sciatic nerve (Bennett and Xie, Pain 33 (1988): 87-107). The second method 10 is to ligate about half the diameter of the common sciatic nerve (Seltzer et% printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs (1990) · 205-218). In another method, a set of modes is used, in which the spinal nerves are tightened and ligated or transected at the L5 and L6 spinal nerves (KIM SH; CHUNG JM? AN EXPERIMENTAL-MODEL FOR PERIPHERAL NEUROPATHY PRODUCED BY 15 SEGMENTAL SPINAL NERVE LIGATION IN THE RA, PAIN 50 (3) (1992): 355-363). The fourth method involves removing the nerve axis of two of the three terminal branches of the sciatic nerve (tibia and common peroneal nerve), leaving the complete gastrocnemius nerve, and the last method is only removing the tibial branch nerve, leaving the sural and The common nerve was unharmed. Animals in the control group received sham surgery. After surgery, nerve-impaired animals develop chronic mechanical hyperalgesia, cold hyperalgesia, and thermal hyperalgesia. Mechanical analgesia is measured using a pressure transducer (Electronic von Frey Anesthesiometer, IITC Inc.-Life Science Instruments, Woodland Hills, -43- US paper size applies to Chinese National Standard (CNS) A4 (210x297 mm) 200404052 Μ Β7 V. Description of the Invention (42) SA, USA; Swedish Electronic von Frey System, Somedic Sales AB, Horby, Sweden) 〇 The thermal hyperalgesia system uses a radiant heat source (foot test: Ugo Basile, Comerio, Italy) to measure or use For cold plate measurement at 5-10 ° C, calculate the foot wound response after the impact in 5 as the measurement of pain intensity. Another cold-induced pain test was to count the number of wound reactions, or measure the length of time that a wound reaction occurred after acetone was administered to the soles of the feet after the impact. Chronic pain usually records its motility physiological clock (Germany

Surjo and Arndt，Universitat zu Koln，Cologne，Germany)及步 10 悲之差異性分數（腳印型態，FOOTPRINTS .program, Klapdor et al5 1997., A low costmethod to analyse footprint patterns· J. Neurosci. Methods 75, 49-54)來分析。化合物在假手術及媒劑處理對照組被測試。進行疼痛試驗之前，在不同時間點，經由不同投藥途徑（靜脈内、 15 腹膜内、口服、鞘内（丨丄）、i.c.v·、皮下、皮内、穿皮式)投與藥物。 [發炎疼痛之測定] 經濟部智慧財產局員工消費合作社印製主要在大老鼠一隻後腳中注射0.75 mg鹿角菜醣或完 20 全弗洛伊德氏輔劑(Freund’s adjuvant)，引發發炎疼痛。以機械性痛覺異常及熱痛覺過敏使動物發展出水腫。機械性痛見異吊係利用壓力轉換器測定（美國Electronic von Frey Anesthesiometer, IITC Inc.-Life Science Instruments, Woodland Hills，SA，USA)。熱痛覺過敏係採用輻射熱源(腳 -44- 本紙張尺度適用中國國家標準(CNS)A4規格（21〇x297公釐） 200404052 A7 B7 五、發明說明（43) 底試驗·義大利Ugo Basile，Comerio，Italy ;腳部熱刺激器，美國加州大學G· Ozaki)測定。採用兩種方法測定水腫。第一種方法，殺死動物，切下受影響之後腳，稱重。第二種方法包括在體積描記器上測量腳部被水置換之體積 5 差異（義大利 Ugo Basile，Comerio, Italy)。化合物在未發炎組及媒劑處理對照組被測試。進行疼痛試驗之前，在不同時間點，經由不同投藥途徑（靜脈内、腹膜内、口服、鞘内、i.c.v.、皮下、皮内、穿皮式) 投與藥物。 10 [糖尿病神經病變性疼痛] 使大老鼠經腹膜内注射一次50-80 mg/kg鏈黴亞硝基素處理，在1-3週内發展出嚴重之高血糖症與機械性痛覺異常。機械性痛覺異常係利用壓力轉換器測定（美國 15 Electronic von Frey Anesthesiometer, IITC Inc.-Life Science Instruments，Woodland Hills，SA，USA)。經濟部智慧財產局員工消費合作社印製化合物在糖尿病組及非糖尿病媒劑處理對照組被測試。進行疼痛試驗之前，在不同時間點，經由不同投藥途徑（靜脈内、腹膜内、口服、鞘内、i.c.v.、皮下、皮内、 20 穿皮式)投與藥物。 / 辣椒素在人類VR1轉感染之CHO細胞株中誘發之 Ca2+流入量結果示於下列實例及實例列表中。其數據係固相合成法所產生化合物之數據，其純度為約40-90%。實際上’化合物可分成下列四級活性： -45- 本纸張尺度適用中國國家標準(CNS)A4規格（210x297公釐） 200404052 A7 B7 五、發明說明（44 ) IC5〇=A(< 或=)0·1μΜ<Β (〈或= )0·5μΜ<(：(< 或=)1Surjo and Arndt, Universitat zu Koln, Cologne, Germany) and step 10 sad difference scores (footprint patterns, FOOTPRINTS.program, Klapdor et al5 1997., A low costmethod to analyse footprint patterns · J. Neurosci. Methods 75, 49-54). Compounds were tested in sham and vehicle-treated controls. Before the pain test, the drug was administered at different time points via different routes of administration (intravenous, 15 intraperitoneal, oral, intrathecal (（), i.c.v., subcutaneous, intradermal, transdermal). [Determination of Inflammation and Pain] Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs. Inject 0.75 mg of carrageenose or 20% Freund's adjuvant into one hind foot of a rat, causing inflammation and pain. Animals develop edema with mechanical hyperalgesia and thermal hyperalgesia. Mechanical pain was measured using a pressure transducer (Electronic von Frey Anesthesiometer, IITC Inc.-Life Science Instruments, Woodland Hills, SA, USA). Thermal hyperalgesia uses a radiant heat source (foot-44- This paper size applies the Chinese National Standard (CNS) A4 specification (21 × 297 mm) 200404052 A7 B7 V. Description of the invention (43) Bottom test · Ugo Basile, Italy , Italy; Foot Thermal Stimulator, University of California, G. Ozaki). Two methods were used to measure edema. The first method is to kill the animal, cut off the affected feet, and weigh. The second method involves measuring the difference in volume of the foot replaced by water on a plethysmograph (Ugo Basile, Italy, Comerio, Italy). Compounds were tested in the non-inflammatory and vehicle-treated control groups. Before the pain test, the drug was administered at different time points via different routes of administration (intravenous, intraperitoneal, oral, intrathecal, i.c.v., subcutaneous, intradermal, transdermal). 10 [Diabetic neuropathic pain] The rats were treated with intraperitoneal injection of 50-80 mg / kg of streptomycin and developed severe hyperglycemia and mechanical hyperalgesia within 1-3 weeks. Mechanical analgesia was measured using a pressure transducer (15 Electronic von Frey Anesthesiometer, IITC Inc.-Life Science Instruments, Woodland Hills, SA, USA). Compounds printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs were tested in the diabetic group and the non-diabetic vehicle treatment control group. Before the pain test, the drug was administered at different time points via different routes of administration (intravenous, intraperitoneal, oral, intrathecal, i.c.v., subcutaneous, intradermal, 20 transdermal). The results of Ca2 + influx induced by capsaicin in human VR1-transfected CHO cell lines are shown in the following examples and list of examples. The data is based on the compound produced by solid-phase synthesis, and its purity is about 40-90%. In fact, 'compounds can be divided into the following four levels of activity: -45- This paper size applies the Chinese National Standard (CNS) A4 specification (210x297 mm) 200404052 A7 B7 V. Description of the invention (44) IC50 = A (< or =) 0 · 1μΜ < B (<or =) 0 · 5μΜ < (: (< or =) 1

μΜ < D 本發明化合物亦在上述其他分析法(2>(5)中展現優越選擇性及強烈活性。起始化合物之製法 [起始化合物Α]μM < D The compound of the present invention also exhibits superior selectivity and strong activity in the other analysis methods described above (2) (5). Preparation method of the starting compound [Starting compound A]

裝Hold

計線Gauge line

經濟部智慧財產局員工消費合作社印製在s 8-胺基_2_奈盼（5〇〇 g，314 mm〇i)之四氫σ夫喃 (1000 mL)攪拌溶液中添加二碳酸二_第三丁酯（68 6匕Η# 20 mm〇1)。混合物於70°C下攪拌18小時。混合物冷卻至室溫後，減壓排除溶劑。在殘質中添加乙酸乙自旨，以飽和碳酸鈉水溶液及水依序洗滌。萃取之有機層經Na2S〇4脫水，過濾，及減壓濃縮。在所得殘質中添加二異丙基醚，過濾 >儿澱，及乾燥，產生N-第三丁氧羰基胺基萘酚 -46-Printed by the Employees' Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs in a stirred solution of tetrahydrosigmafuran (1000 mL) in s 8-amino_2_napan (500g, 314 mm) with di_carbonate di_ Third butyl ester (68 6 dagger # 20 mm). The mixture was stirred at 70 ° C for 18 hours. After the mixture was cooled to room temperature, the solvent was removed under reduced pressure. Ethyl acetate was added to the residue, and the mixture was washed sequentially with a saturated sodium carbonate aqueous solution and water. The extracted organic layer was dehydrated over Na2SO4, filtered, and concentrated under reduced pressure. To the obtained residue, diisopropyl ether was added, filtered > Yodo, and dried to give N-third butoxycarbonylaminonaphthol -46-

200404052 A7 B7 五、發明說明（45) (64.2g，收率 79°/〇)。 MS(ESI) m/z 259[M]+ 4 NMR (DMSO-d6)5 1.48 (s，9H)，7·07 (dd，J= 2·2 Hz 與 8.85 Hz，H)，7·20 (t，7.9 Hz，1H)，7.24 (d，J= 2.2 Hz，1H)， 5 7.36 (d，J= 7.25 Hz，1H)，7.60 (d，J= 8·2Ηζ，1H)，7.75 (d，J= 8.8 Hz，1H)，8.92(s，1H) 〇200404052 A7 B7 V. Description of the invention (45) (64.2g, yield 79 ° / 〇). MS (ESI) m / z 259 [M] + 4 NMR (DMSO-d6) 5 1.48 (s, 9H), 7.07 (dd, J = 2.2 Hz and 8.85 Hz, H), 7.20 ( t, 7.9 Hz, 1H), 7.24 (d, J = 2.2 Hz, 1H), 5 7.36 (d, J = 7.25 Hz, 1H), 7.60 (d, J = 8 · 2Ηζ, 1H), 7.75 (d, J = 8.8 Hz, 1H), 8.92 (s, 1H).

其次，於室溫下，在含N-第三丁氧羰基-8-胺基-2-萘酚（64.0 g，247 mmol)與碳酸鉋（161 g，493mm〇1)i 3〇〇 mL 無水DMF混合物中添加碘乙烷(42·3 g，272 mm〇l)。混合 10物於60 C下擾拌2小時。加水至混合物中，以乙酸乙酯萃取產物。有機層經水與鹽水洗滌，經硫酸鈉脫水，過渡及減壓濃縮。在所得殘質中添加二異丙醚，收集沉澱，及乾燥，產生(7-乙氧基-萘小基)胺甲酸第三丁酯(47.9 g，收率 67.5 %) 〇 15 MS (ESI) m/z 287 [M]+ !H NMR (DMSO-d6) δ Ml (t，J= 6·95 Hz，3H)，1.50 (s，9H) 4.16 (q，J= 6.95 Hz，2H)，7.15 (dd，J= 2.55 與 8·8Ηζ，1H) 7.28 (t，J= 8·8 Hz，1H)，7.36 (d，J= 2.2 Hz，lH)，7.54 (d j= 經濟部智慧財產局員工消費合作社印製 7·25 Hz，1H)，7.61 (d，J= 8·2 Hz，1H)，7.80 (d，J= 8.85 Hz 20 lH)，9.12(s，1H)。 ’ 其次，於0°C下，在含(7-乙氧基-萘小基 > 胺曱酸第三丁酯（47.9 g，167 mmol)之100 mL無水1，4-二α号烧中添加 4Ν HC1之Μ-二啐烷（lOOmL)溶液。混合物於室溫下授掉 2小時。添加二異丙鱗至反應混合物中，過濾沉殺。在所 -47- 本紙張尺度適用中國國家標準(CNS)A4規格（210x297公釐） 200404052 A7 B7 五、發明說明（46 ) 15 得固體中添加飽和碳酸氫鈉溶液，以乙酸乙酯萃取產物。有機層經硫酸鈉脫水，過濾及減壓濃縮，產生7-乙氧基_ 萘小基胺(27.0 g，收率86.3 %)。 MS (ESI) m/z 187 [M]+ 'H NMR (DMSO-d6) 5 1.39 (t,J= 11.3 Hz, 3H)? 4.15 (q? J== 11.3 Hz，2H)，5.52(s(br)，2H)，6·64 (dd，J= 3.75 與 i〇〇5 Hz 1H)，7.01-7.07 (m，3H)，7.39 (d，J=3.8 Hz，1H)，7.63 (d j= 14.45 Hz，1H) 〇其次’於_78C下’在含7-乙氧基·萘-i-基胺（18〇 g，9.61 mmol)與第三丁醇（2·13 g，28.8 mmol)之四氫吱喃（20 mL)混合物之燒瓶中收集液態氨(300 mL)。於30分鐘内，在混合物中添加經(0.200 g，28.8 mmol)，於_78。(3下授拌1 小時。添加甲醇與水，混合物於室溫下攪拌16小時，使氨蒸發。在所得殘質中添加乙酸乙酯。有機層經水洗滌，經硫酸鈉脫水，過濾及減壓濃縮，產生7_乙氧基乃，8-二氫萘-1-基胺（1.37 g，收率76%)。 [起始化合物B] 經濟部智慧財產局員工消費合作社印製 20Secondly, at room temperature, in a solution containing N-third butoxycarbonyl-8-amino-2-naphthol (64.0 g, 247 mmol) and carbon shavings (161 g, 493 mm1) i 300 mL of anhydrous To the DMF mixture was added iodoethane (42.3 g, 272 mm). Mix the contents and stir at 60 C for 2 hours. Water was added to the mixture, and the product was extracted with ethyl acetate. The organic layer was washed with water and brine, dried over sodium sulfate, transitioned and concentrated under reduced pressure. Diisopropyl ether was added to the obtained residue, and the precipitate was collected and dried to give (7-ethoxy-naphthalene small) carbamic acid third butyl ester (47.9 g, yield 67.5%). 15 MS (ESI) m / z 287 [M] +! H NMR (DMSO-d6) δ Ml (t, J = 6.95 Hz, 3H), 1.50 (s, 9H) 4.16 (q, J = 6.95 Hz, 2H), 7.15 (dd, J = 2.55 and 8.8Ηζ, 1H) 7.28 (t, J = 8.8 Hz, 1H), 7.36 (d, J = 2.2 Hz, lH), 7.54 (dj = employee consumption of Intellectual Property Bureau, Ministry of Economic Affairs) The cooperative prints 7.25 Hz, 1H), 7.61 (d, J = 8.2 Hz, 1H), 7.80 (d, J = 8.85 Hz 20 lH), 9.12 (s, 1H). '' Secondly, at 0 ° C, in 100 mL of anhydrous 1,4-di-α-carbonate containing (7-ethoxy-naphthalene small group) tertiary butyl amino acid (47.9 g, 167 mmol) Add 4N HC1 in M-dioxane (100mL) solution. The mixture is allowed to incubate for 2 hours at room temperature. Diisopropyl scale is added to the reaction mixture, and filtered and killed. The paper size applies to Chinese national standards. (CNS) A4 specification (210x297 mm) 200404052 A7 B7 V. Description of the invention (46) 15 A saturated sodium bicarbonate solution was added to the obtained solid, and the product was extracted with ethyl acetate. The organic layer was dehydrated with sodium sulfate, filtered and concentrated under reduced pressure. , Yielding 7-ethoxy_naphthalene small amine (27.0 g, yield 86.3%). MS (ESI) m / z 187 [M] + 'H NMR (DMSO-d6) 5 1.39 (t, J = 11.3 Hz, 3H)? 4.15 (q? J == 11.3 Hz, 2H), 5.52 (s (br), 2H), 6.64 (dd, J = 3.75 and IOHz 1H), 7.01-7.07 ( m, 3H), 7.39 (d, J = 3.8 Hz, 1H), 7.63 (dj = 14.45 Hz, 1H) 〇 followed by 'under _78C' containing 7-ethoxy · naphthalene-i-ylamine (18 〇g, 9.61 mmol) and tert-butanol (2.13 g, 28.8 mmol) in a mixture of tetrahydrofuran (20 mL) in a flask Ammonia (300 mL). Within 30 minutes, add (0.200 g, 28.8 mmol) to the mixture at _78. (Stir for 3 hours under 3 hours. Add methanol and water, stir the mixture at room temperature for 16 hours The ammonia was evaporated. Ethyl acetate was added to the obtained residue. The organic layer was washed with water, dehydrated with sodium sulfate, filtered, and concentrated under reduced pressure to give 7-ethoxynaphthalene, 8-dihydronaphthalen-1-ylamine. (1.37 g, yield 76%). [Starting Compound B] Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economy 20

在3 7-乙氧基_5,8-二氫萘-1-基胺（1〇7g，5.65 _〇1)之 -48-Among 3 7-ethoxy-5,8-dihydronaphthalen-1-ylamine (107 g, 5.65 _01) -48-

200404052 A7 B7 五、發明說明（47 ) 四氫呋喃（30 mL)攪拌溶液中添加2N HC1水溶液（1〇 mL)，於40°C下撥拌1小時。混合物經添加礙酸氫納中和，以乙酸乙酯萃取產物。有機層以水洗滌，經硫酸鈉脫水，過濾及減壓濃縮，產生8-胺基-3,4-二氫-1H-萘-2-酮（0.71 g，收 5 率 78%) 〇 MS(ESI)m/z 162[M+H]+ lH NMR (CDC13)(5 2.62-2.65 (m, 2H), 3.07 (t?J= 7.25 Hz, 2H)，3.34(s，2H)，6.65(d，J= 7.85, 1H)，6·70 (d，J= 7.25 Hz，1H)， 7.07(t, J=7.55Hz, 1H)。 10 其次，於〇°C下，在含8-胺基-3,4-二氫-1H-萘-2-酮 (0·〇5〇 g，0.318 mmol)之曱醇（10 mL)中添加氫棚化納（0.030 g, 0.175 mmol)，混合物攪拌1小時。混合物倒至水中，以乙酸乙酯萃取產物。有機層經硫酸鈉脫水，過濾，及減壓濃縮，產生8-胺基-1，2,3,4-四氫-萘-2_酚(0.037 g，收率 15 71 %)。 MS(ESI)m/z 163 [M]+ 經濟部智慧財產局員工消費合作社印製 ^MR (DMSO-d6) δ 1.53-1.57 (m? 1H), 1.81-1.85 (m, 1H)，2.16 (dd，J= 7·7 與 16.4 Hz, 1H)，2.61-2.74 (m，3H)， 3.89-3.90 (m，1H)，4.65 (s，2H)，4.72 (d，J= 4.1 Hz，lH)，6.28 20 (d，J= 7·45 Hz，1H)，6.28 (d，J= 7·45 Hz，1H)，6·41 (d，J- 7·7200404052 A7 B7 V. Description of the invention (47) 2N HC1 aqueous solution (10 mL) was added to a stirred solution of tetrahydrofuran (30 mL), and stirred at 40 ° C for 1 hour. The mixture was neutralized by the addition of sodium hydroxide, and the product was extracted with ethyl acetate. The organic layer was washed with water, dehydrated with sodium sulfate, filtered and concentrated under reduced pressure to give 8-amino-3,4-dihydro-1H-naphthalene-2-one (0.71 g, yield 5% 78%). ESI) m / z 162 [M + H] + lH NMR (CDC13) (5 2.62-2.65 (m, 2H), 3.07 (t? J = 7.25 Hz, 2H), 3.34 (s, 2H), 6.65 (d , J = 7.85, 1H), 6.70 (d, J = 7.25 Hz, 1H), 7.07 (t, J = 7.55 Hz, 1H). 10 Second, at 0 ° C, containing 8-amino groups- To 3,4-dihydro-1H-naphthalen-2-one (0.050 g, 0.318 mmol) in methanol (10 mL) was added hydrogen shed sodium (0.030 g, 0.175 mmol), and the mixture was stirred for 1 hour. The mixture was poured into water and the product was extracted with ethyl acetate. The organic layer was dehydrated over sodium sulfate, filtered, and concentrated under reduced pressure to give 8-amino-1,2,3,4-tetrahydro-naphthalene-2_phenol ( 0.037 g, yield 15 71%). MS (ESI) m / z 163 [M] + printed by the Consumer Cooperative of Intellectual Property Bureau of the Ministry of Economic Affairs ^ MR (DMSO-d6) δ 1.53-1.57 (m? 1H), 1.81 -1.85 (m, 1H), 2.16 (dd, J = 7.7 and 16.4 Hz, 1H), 2.61-2.74 (m, 3H), 3.89-3.90 (m, 1H), 4.65 (s, 2H), 4.72 (d, J = 4.1 Hz, lH), 6.28 20 (d, J = 7.45 Hz, 1H), 6.28 (d, J = 7.45 Hz, 1H), 6.41 (d, J- 7 · 7

Hz, lH)，6.76(t，J=7.55Hz，lH)。 [起始化合物C] -49- 本紙張尺度適用中國國家標準(CNS)A4規格（210x297公釐） 200404052 A7 B7 五、發明說明（48)Hz, lH), 6.76 (t, J = 7.55Hz, lH). [Starting Compound C] -49- This paper size is applicable to China National Standard (CNS) A4 (210x297 mm) 200404052 A7 B7 V. Description of the invention (48)

5 於氬氣下，取含苯釕（II)氯化物二聚物（3.10 mg， 0.006mmol)與（lS，2R)-(-)-順式小胺基-2-茚滿醇（3·7 mg， 0.025 mmol)之脫氣異丙醇混合物於80°C下攪拌加熱20分鐘。於室溫下，將混合物加至含8-胺基-3,4-二氫-1H-萘-2-10 酮（50 mg，0.310 mmol)之異丙醇(3 mL)溶液中。添加含氫氧化卸(3.48 mg，0.062 mmol)之異丙醇（lmL)溶液，混合物於45°C下攪拌1小時。使混合物通過矽膠，以乙酸乙酯洗滌。濾液減壓濃縮，產生對掌性8-胺基-1，2,3,4-四氫-萘-2-酚對映異構物(33.0 mg，收率65 %)。 15 MS(ESI)m/z 163 [M]+ 經濟部智慧財產局員工消費合作社印製 lU NMR (DMSO-d6) 5 1.53-1.57 (m，1H)，1.81-1.85 (m，1H)， 2.16 (dd，J= 7.7 與16.4 1^，1«〇,2.61-2.74(111，311)，3.89-3.90 (m，1H)，4.65 (s，2H)，4·72 (d，J= 4·1 Hz，1H)，6·28 (d， J= 7.45 Hz，1H)，6.28 (d，J= 7.45 Hz，1H)，6.41 (d，J= 7.7 Hz， 20 1H)，6-76(t，J= 7·55 Hz，1H) 〇 [起始化合物D] -50- 本紙張尺度適用中國國家標準(CNS)A4規格（210 x 297公釐） 200404052 A7 ____ B7 五、發明說明（49)5 Under argon, take benzene-ruthenium (II) chloride dimer (3.10 mg, 0.006 mmol) and (1S, 2R)-(-)-cis-small amino-2-indanol (3 · 7 mg, 0.025 mmol) of a degassed isopropanol mixture was stirred and heated at 80 ° C for 20 minutes. The mixture was added to a solution of 8-amino-3,4-dihydro-1H-naphthalene-2-10one (50 mg, 0.310 mmol) in isopropanol (3 mL) at room temperature. A solution of hydrogen peroxide (3.48 mg, 0.062 mmol) in isopropanol (1 mL) was added, and the mixture was stirred at 45 ° C for 1 hour. The mixture was passed through silica gel and washed with ethyl acetate. The filtrate was concentrated under reduced pressure to give p-palm 8-amino-1,2,3,4-tetrahydro-naphthalene-2-phenol enantiomer (33.0 mg, yield 65%). 15 MS (ESI) m / z 163 [M] + Printed by 1U NMR (DMSO-d6) of the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economy 5 1.53-1.57 (m, 1H), 1.81-1.85 (m, 1H), 2.16 (dd, J = 7.7 and 16.4 1 ^, 1 «〇, 2.61-2.74 (111, 311), 3.89-3.90 (m, 1H), 4.65 (s, 2H), 4.72 (d, J = 4 · 1 Hz, 1H), 6.28 (d, J = 7.45 Hz, 1H), 6.28 (d, J = 7.45 Hz, 1H), 6.41 (d, J = 7.7 Hz, 20 1H), 6-76 (t , J = 7.55 Hz, 1H) 〇 [starting compound D] -50- The paper size is applicable to China National Standard (CNS) A4 (210 x 297 mm) 200404052 A7 ____ B7 V. Description of the invention (49)

5 取含苯釕(II)氯化物二聚物（155g)與（1S，2R)七)_順式小胺基-2-節滿醇（l.85g)之脫氣異丙醇(5〇〇mL)攪拌溶液於8〇 C與氬氣下攪拌20分鐘，然後冷卻至室溫。於室溫下， 10將混合物加至含8-胺基-3,‘二氫_1H_萘_2_酮（25.0g)之異丙醇(700 mL)溶液中後，添加氫氧化卸（174§)於3〇〇1^異丙醇中製成之溶液（先於45°C下製備，以便溶解後冷卻至室溫）。混合物於45°C下攪拌30分鐘後，使混合物冷卻至室溫後，通過矽膠墊，以乙酸乙酯洗滌。濾液減壓濃 15縮，所得固體溶於二氯曱烷中，以活性碳處理1〇分鐘。經矽膠墊過濾後，混合物減壓濃縮。所得產物自二氯曱烷中再結晶，產生(R)-8-胺基-1，2,3,4-四氫-萘_2_酚紅色結晶 (14g，收率 56 %)。經濟部智慧財產局員工消費合作社印製 MS(ESI)m/z 163 [M]+ 20 HNMR (DMSO-d6) 5 1.53-1.57 (m5 1H), L81-1.85 (m, 1H)? 2.16 (dd，J= 7.7 與16.4取1印，2.61-2.74(111，3印，3.89-3.90 (m，1H)，4.65 (s，2H)，4.72 (d，4·1 Hz，1H)，6.28 (d，J =7.45 Hz，1H)，6·28 (d，7·45 Hz，1H)，6.41 (d，7.7 Hz， lH)，6.76(t，J= 7.55 Hz，1H)。 -51- 本紙張尺度適用中國國家標準(CNS)A4規格（210x297公爱） 200404052 A7 B75 Take benzene ruthenium (II) chloride dimer (155 g) and (1S, 2R) hepta) -cis-small amino-2-benzanol (1.85 g) of degassed isopropanol (50. (0 mL) was stirred at 80 ° C under argon for 20 minutes, and then cooled to room temperature. The mixture was added to a solution containing 8-amino-3, 'dihydro_1H_naphthalene_2_one (25.0g) in isopropanol (700 mL) at room temperature, and then added with hydrogen hydroxide ( 174§) A solution made in 3,000 ^ isopropanol (prepared at 45 ° C so as to cool to room temperature after dissolution). After the mixture was stirred at 45 ° C for 30 minutes, the mixture was cooled to room temperature, and then passed through a silica gel pad and washed with ethyl acetate. The filtrate was concentrated under reduced pressure and the solid was dissolved in dichloromethane and treated with activated carbon for 10 minutes. After filtering through a pad of silica gel, the mixture was concentrated under reduced pressure. The resulting product was recrystallized from dichloromethane, yielding (R) -8-amino-1,2,3,4-tetrahydro-naphthalene_2-phenol red crystals (14 g, yield 56%). Printed MS (ESI) m / z 163 [M] + 20 HNMR (DMSO-d6) 5 1.53-1.57 (m5 1H), L81-1.85 (m, 1H)? 2.16 (dd , J = 7.7 and 16.4 take 1 mark, 2.61-2.74 (111, 3 marks, 3.89-3.90 (m, 1H), 4.65 (s, 2H), 4.72 (d, 4.1 Hz, 1H), 6.28 (d , J = 7.45 Hz, 1H), 6.28 (d, 7.45 Hz, 1H), 6.41 (d, 7.7 Hz, lH), 6.76 (t, J = 7.55 Hz, 1H). -51- This paper Standards apply to China National Standard (CNS) A4 specifications (210x297 public love) 200404052 A7 B7

五、發明說明（5〇使用（1R，2SH+)-順式小胺基-2_節滿醇產生⑻各胺基_ 1，2,3,4-四氮《•茶-2-紛。其次’取含⑻胺基-I，2,3,4,氫·萘冬驗(π·2 g)與 0比0疋（18.8 ml)之THF(850 ml)溶液於〇。〇下冷卻，添加氯曱 5 酸苯酯（28.8 ml)。混合物於室溫下攪拌3小時，然後倒至乙酸乙醋中。混合物經NH4C1水溶液與水依序洗滌，有機層經硫酸鈉脫水，過濾及減壓濃縮。在所得殘質中添加乙腈，收集沉澱，以乙腈與二異丙醚(2:3)之藏合物洗務’得到{(R>7-羥基-5,6,7,8-四氫·萘小基卜胺f酸苯醋（33.〇g)。 10 MS (ESI) m/z 284 [M+H]+ ^MR (DMSO-d6) (5 1.59-1.64 (m，lH)，1·83-1·89 (m，1Ή)， 2.68-2.99 (m，4Η)，3·90-3·92 (m，1H)，4.S4 (dd，J== 3·8 Hz 與 29.9 Hz，1H)，6·75 (d，JN 7·9 Hz，1Η)，7·〇>7·25(ΐη，6H)，7·42 (t，J=7.85Hz，lH)，9.29(s，1H)。 15 f例1-1 广 N-[4-氯-3-(三氟甲基)苯基]-N，-(7-經基-5A7,8-四鼠小4基) 脲經濟部智慧財產局員工消費合作社印製 20V. Description of the invention (50) The use of (1R, 2SH +)-cis-small amine-2-benzyl alcohol produces each amine group 1,2,3,4-tetrazine "• tea-2-fan. Second 'Take a solution containing amido-I, 2,3,4, hydronaphthol (π · 2 g) and 0 to 01 (18.8 ml) in THF (850 ml) at 0. Phenyl chloroacetate 5 acid (28.8 ml). The mixture was stirred at room temperature for 3 hours, and then poured into ethyl acetate. The mixture was sequentially washed with NH4C1 aqueous solution and water, and the organic layer was dehydrated with sodium sulfate, filtered and concentrated under reduced pressure. Acetonitrile was added to the obtained residue, and the precipitate was collected and washed with a Tibetan compound of acetonitrile and diisopropyl ether (2: 3) to obtain {(R > 7-hydroxy-5,6,7,8-tetrahydro Naphthylpyridylamine f acid benzoate (33.0 g). 10 MS (ESI) m / z 284 [M + H] + MR (DMSO-d6) (5 1.59-1.64 (m, lH), 1.83-1 · 89 (m, 1Ή), 2.68-2.99 (m, 4Η), 3.90-3 · 92 (m, 1H), 4.S4 (dd, J == 3 · 8 Hz and 29.9 Hz, 1H), 6.75 (d, JN 7.9 Hz, 1Η), 7.0 ·> 25 (ΐη, 6H), 7.42 (t, J = 7.85Hz, 1H), 9.29 ( s, 1H). 15 f Example 1-1 NN- [4-chloro-3- (trifluoromethyl) phenyl] -N,-(7-Cyclo-5A7,8-tetramuscular small 4 (Base) Urea Printed by Consumer Cooperatives, Intellectual Property Bureau, Ministry of Economy 20

F F 本紙張尺度適用中國國家標準(CNS)A4規格（210x297公釐）經濟部智慧財產局員工消費合作社印製 200404052 A7 B7 五、發明說明（Μ) 此實例依據一般方法F進行。在含7-乙氧基-5,8-一氳萘基胺(〇.16g，〇.84mm〇i)之四氫呋喃（15 mL)攪拌溶液中添加異氰酸4_氯_3_三氟甲基_苯酯（0·22 g，l.〇 mm〇l)。混合物於室溫下攪拌15小時後， 5倒至水中。以乙酸乙酯萃取產物，有機層經硫酸鈉脫水，過濾，減壓濃縮，產生N-(4-氯-3-三氟甲基·苯基)_N，_(孓乙氧基-5,8-二氫-萘小基)脲（〇·3ΐ g，收率。/〇)。其次，在含 N-(4-氯-3-二氟曱基-本基)-N’_(7-乙氧基_5,8-二氫-萘-1-基)· 脲(〇·21 g，0.51 mmol)之四氫呋喃（20mL)溶液中添加^^鹽 10酸水溶液(5 mL)，混合物於40。(：下攪拌45分鐘。混合物經添加10 %碳酸氩納溶液中和，以乙酸乙酯萃取。有機層經硫酸鈉脫水，過濾；及減壓濃縮，產生沁(4_氯-3_三氣甲基-苯基)-N47-氧代-5,6,7,8-四氫·萘-i•基)脲(〇16 g，收率85%)。其次，於（TC下，在含队(4_氯冬三氟甲基-苯 15 基)_N，分氧代_5,6,7,8_四氫萘基)腺(〇〇7 g，〇18 麵〇1) 之甲醇（10 mL)溶液中添加氫硼化鈉（0 04 g，〇〇9 mm〇1)，混合物攪拌30分鐘。混合物倒至水中，以乙酸乙酯萃取產物。有機層經硫酸鈉脫水，過濾，減壓濃縮，所得產物自乙酸乙酯/己烷（1/2)溶液中結晶，產生怵[4_氣_3_(三氟 20 甲基)苯基]-Ν，-(7-經基 59%) NMR (DMSO-d6) 5 1.57-1.58 (m, 1H),1.87-1.90 (m, 1H), 2.36-2.42 (m, 1H),2.63-2.76 (m, m), 2.83-2.87 (m, 2H), 3.91-3.96 (m, 1H), 4.87 (d, J= 4.1 Hz, lH),6.82(d, J= 7.6 Hz, 1H), -53-F F This paper size applies to China National Standard (CNS) A4 (210x297 mm) Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs 200404052 A7 B7 V. Description of the Invention (M) This example is performed according to the general method F. To a stirred solution of 7-ethoxy-5,8-mononaphthylamine (0.16 g, 0.84 mm) in tetrahydrofuran (15 mL) was added 4_chloro_3_trifluoromethane isocyanate. -Phenyl ester (0.22 g, 1.0 mm). After the mixture was stirred at room temperature for 15 hours, 5 was poured into water. The product was extracted with ethyl acetate, and the organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure to give N- (4-chloro-3-trifluoromethylphenyl) _N, _ (fluorenylethoxy-5,8 -Dihydro-naphthalene small group) urea (0.3 g, yield./〇). Secondly, N- (4-chloro-3-difluorofluorenyl-benzyl) -N '_ (7-ethoxy-5,8-dihydro-naphthalen-1-yl) · urea (〇 · To a solution of 21 g, 0.51 mmol) of tetrahydrofuran (20 mL) was added ^ salt 10 acid aqueous solution (5 mL), and the mixture was at 40. (: Stirred for 45 minutes. The mixture was neutralized by adding 10% sodium bicarbonate solution, and extracted with ethyl acetate. The organic layer was dehydrated with sodium sulfate, filtered; and concentrated under reduced pressure to produce Q_ (4-chloro-3_three gas) Methyl-phenyl) -N47-oxo-5,6,7,8-tetrahydronaphthalene-i • yl) urea (0 16 g, yield 85%). Secondly, at (TC, in the group containing (4-chlorodongtrifluoromethyl-phenyl 15-yl) _N, oxo_5,6,7,8_tetrahydronaphthyl) gland (〇7 g, To a solution of MeOH (10 mL) in MeOH (10 mL) was added sodium borohydride (0.04 g, 009 mm), and the mixture was stirred for 30 minutes. The mixture was poured into water and the product was extracted with ethyl acetate. The organic layer was dehydrated with sodium sulfate, filtered, and concentrated under reduced pressure. The resulting product was crystallized from an ethyl acetate / hexane (1/2) solution to produce hydrazone [4_Ga_3_ (trifluoro20methyl) phenyl]- Ν,-(7-Cyclo 59%) NMR (DMSO-d6) 5 1.57-1.58 (m, 1H), 1.87-1.90 (m, 1H), 2.36-2.42 (m, 1H), 2.63-2.76 (m , m), 2.83-2.87 (m, 2H), 3.91-3.96 (m, 1H), 4.87 (d, J = 4.1 Hz, lH), 6.82 (d, J = 7.6 Hz, 1H), -53-

200404052 A7 B7 五、發明說明（52) 7.06 (t，J= 7·6 Hz，1H)，7.58 (d，J= 7·6 Hz，1H)，7.61-7·62(ιη， 2H)，7.93 (s，1H)，8.09 (s，1H)，9.47 (s，1H)。200404052 A7 B7 V. Description of the invention (52) 7.06 (t, J = 7.6 Hz, 1H), 7.58 (d, J = 7.6 Hz, 1H), 7.61-7.62 (ιη, 2H), 7.93 (s, 1H), 8.09 (s, 1H), 9.47 (s, 1H).

分子量：384.8 MS (M+H): 384 5 mp: 227-228〇CMolecular weight: 384.8 MS (M + H): 384 5 mp: 227-228〇C

活體外活性等級：A 實例1-2 N-[4_氣_3-(二氣甲基）苯基]_N’-{(R)-7-經基_5,6,7,8-四氮-1_ 10 萘基}脲In vitro activity level: A Example 1-2 N- [4_ 气 _3- (digasmethyl) phenyl] _N '-{(R) -7-Cyclo-5,6,7,8-tetra Nitrogen-1_ 10 naphthyl} urea

經濟部智慧財產局員工消費合作社印製取N-[4_氯-3-(三氟甲基）苯基]-N’-(7-羥基-5,6,7,8-四氫-1-萘基）脲(30.0 mg)之消旋混合物經對掌性HPLC(Daicel OD管柱，正己烷:2-丙醇=98 : 2)分離出相應之R-異構物 20 (8·3 mg) 〇對掌性 HPLC(ChiralCel OD 0.49 cm X 25 cm 管柱，正己烷/乙醇=97/3，流速1·5 mL/分鐘），於20.1分鐘時檢測到R-異構物。分子量：384.8 -54- 本紙張尺度適用中國國家標準(CNS)A4規格（210x297公釐） 200404052 A7 B7 五、發明說明（53 ) MS(M+H):384 實例1-3 N-[4-氣-3-(三氟甲基）苯基]-N’-{(S)-7-羥基-5,6,7,8-四氫-1-5 萘基}脲Printed by N- [4_chloro-3- (trifluoromethyl) phenyl] -N '-(7-hydroxy-5,6,7,8-tetrahydro-1 -Naphthyl) urea (30.0 mg) racemic mixture was separated by corresponding palm HPLC (Daicel OD column, n-hexane: 2-propanol = 98: 2) to separate the corresponding R-isomer 20 (8 · 3 mg) 〇 On palm HPLC (ChiralCel OD 0.49 cm X 25 cm column, n-hexane / ethanol = 97/3, flow rate 1.5 mL / min), R-isomers were detected at 20.1 minutes. Molecular weight: 384.8 -54- This paper size is applicable to Chinese National Standard (CNS) A4 specification (210x297 mm) 200404052 A7 B7 V. Description of the invention (53) MS (M + H): 384 Example 1-3 N- [4- 3- (trifluoromethyl) phenyl] -N '-{(S) -7-hydroxy-5,6,7,8-tetrahydro-1-5 naphthyl} urea

經濟部智慧財產局員工消費合作社印製取N_[4_氣-3-(三氟甲基)苯基]_N47_羥基-5,6,7,8-四氫-1-萘基）脲(30·0 mg)之消旋混合物經對掌性HPLC(Daicel 15 OD管柱，正己烷:2_丙醇=98 : 2)分離出相應之S-異構物 (2.2mg)。對掌性 HPLC(ChiralCel OD 0·49 cm X 25 cm 管柱，正己烷/乙醇=97/3，流速1.5 mL/分鐘），於17.6分鐘時檢測到S-異構物。 20 分子量：384.8 MS(M+H):384 實例2-1 N-苯基基-5，6,7,8·四鼠-1-奈基) -55- 本紙張尺度適用中國國家標準(CNS)A4規格（210x297公釐） 200404052 A7 B7N_ [4_Ga-3- (trifluoromethyl) phenyl] _N47_hydroxy-5,6,7,8-tetrahydro-1-naphthyl) urea (printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs) The racemic mixture at 30 · 0 mg) was separated by corresponding palm HPLC (Daicel 15 OD column, n-hexane: 2-propanol = 98: 2) to separate the corresponding S-isomer (2.2 mg). For palm HPLC (ChiralCel OD 0.49 cm X 25 cm column, n-hexane / ethanol = 97/3, flow rate 1.5 mL / min), the S-isomer was detected at 17.6 minutes. 20 Molecular weight: 384.8 MS (M + H): 384 Example 2-1 N-phenyl-5,6,7,8 · tetramurine-1-nyl) -55- This paper size applies to Chinese National Standards (CNS ) A4 size (210x297 mm) 200404052 A7 B7

五Fives

HOHO

此實例依據一般方法A進行。於室溫下’在含8-胺基-1，2,3,4-四氫_萘_2_醇（2〇〇吨 10 Μ-二号烷(1·〇 mL)溶液中添加異氰酸苯醋 (14.6 mg，0.123 mmol) 〇混合物攪拌 1 見什小時後，添加二異丙醚與己烧。過遽沉殿’及乾燥，產生N_苯基界(7_經基-5,6,7,8-四氫-1-萘基)脲（17.8]11§，收率51^/)This example is performed according to General Method A. Isocyanide was added to a solution containing 8-amino-1,2,3,4-tetrahydro-naphthalene-2-ol (200 tons of 10 M-dioxane (1.0 mL) at room temperature. Acid phenyl vinegar (14.6 mg, 0.123 mmol). After the mixture was stirred for 1 hour, diisopropyl ether and hexane were added. After passing through Shen Dian'an and drying, N_phenyl group (7_ meridyl-5, 6,7,8-tetrahydro-1-naphthyl) urea (17.8) 11§, yield 51 ^ /)

分子量：282.3 MS(M+H):283 15 mp: 198-199〇C 活性等級：C 使用起始物B並類似上述實例n ^ <方法，合成實例 2-2至2-41並測試。經濟部智慧財產局員工消費合作社印製 -56- 本紙張尺度適用中國國家標準(CNS)A4規格（210 X 297公釐） 200404052 經濟部智慧財產局員工消費合作社印製 A7 B7 五、發明說明（55 ) 表1Molecular weight: 282.3 MS (M + H): 283 15 mp: 198-199 ° C Activity grade: C Using starting material B and similar to the method of Example n ^ above, Examples 2-2 to 2-41 were synthesized and tested. Printed by the Employees' Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs-56- This paper size applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) 200404052 Printed by the Consumers ’Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs A7 B7 V. Description of the invention ( 55) Table 1

實你臟分子結構式 MW MS MP 活性等級 2-2 入α Χό 316,79024 317 197-199 B 2-3 νΛ〇, Λ χό. 316,79024 317 216-218 A 2-4 . Ν人。 Χό 316,79024 317 229-231 A 2-5 A 入& ηοό6 . 312,3717 313 187-189 B -57- 本紙張尺度適用中國國家標準(CNS)A4規格（210 X 297公釐） 200404052 A7 B7 五、發明說明（56 ) 經濟部智慧財產局員工消費合作社印製Real dirty molecular structure MW MS MP Activity level 2-2 into α Χό 316,79024 317 197-199 B 2-3 νΛ〇, Λ χό. 316,79024 317 216-218 A 2-4. Ν. Ⅹ 316,79024 317 229-231 A 2-5 A In & ηοό6. 312,3717 313 187-189 B -57- This paper size applies to China National Standard (CNS) A4 (210 X 297 mm) 200404052 A7 B7 V. Description of Invention (56) Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs

實作臟分子結構式 MW MS MP 活性等級 2-6 N人0 X0 312,3717 313 213-215 D 2-7 .¾ N太0 . 350,34359 351 217-219 C 2-8 N^O ΗΧό 350,34359 351 227-228 A 2-9 Ν人0 ηοό6 350,34359 351 222-224 A -58- 本紙張尺度適用中國國家標準(CNS)A4規格（210x297公釐） 200404052 經濟部智慧財產局員工消費合作社印製 A7 B7 五、發明說明（57 ) 實作贼分子結構式 MW MS ΜΡ ，活性等級 2-10 CH, V ' ，入 Τό 354,40934 355 178-180 D 2-11 ΗχΧγ°^ Ά Τ Χό. 354,40934 355 176-178 A 2-12 ..成 Ν八〇 Χό .354,40934 355 204-206 A 2-13 ΝΙ$) Χό 332,40575 333 250-252 A -59- 本紙張尺度適用中國國家標準(CNS)A4規格（210 X 297公釐） 200404052 A7 B7 五、發明說明（58) 經濟部智慧財產局員工消費合作社印製實你藏分子結構式 MW MS MP · 活性等級 2-14 霜 NI人。 Χό 332,40575 333 212-214 A 2-15 • Ν人。 300,33564 301 214-216 B 2-16 '众入· 361,24124 362 237-239 A 2-17 .XX： Ν人0 Τ0 351,23527 352 234-235 A -60- 本紙張尺度適用中國國家標準(CNS)A4規格（210x297公釐）經濟部智慧財產局員工消費合作社印製 200404052 A7 B7 五、發明說明（59 )Implementation of dirty molecular structural formula MW MS MP Activity level 2-6 N human 0 X0 312, 3717 313 213-215 D 2-7 .¾ N too 0. 350,34359 351 217-219 C 2-8 N ^ O ΗΧό 350,34359 351 227-228 A 2-9 Ν person 0 ηοό6 350,34359 351 222-224 A -58- This paper size applies to China National Standard (CNS) A4 (210x297 mm) 200404052 Employees of the Intellectual Property Bureau of the Ministry of Economic Affairs Printed by the Consumer Cooperative A7 B7 V. Description of the invention (57) Implementation of the molecular structure formula MW MS MP of the thief, activity level 2-10 CH, V ', entered Τ, 354,40934 355 178-180 D 2-11 Ηχχγ ° ^ Ά Τ Χ. 354,40934 355 176-178 A 2-12: Cheng N 〇〇〇. .354,40934 355 204-206 A 2-13 ΝΙ $) 332,40575 333 250-252 A -59- this paper Standards are applicable to China National Standard (CNS) A4 specifications (210 X 297 mm) 200404052 A7 B7 V. Description of invention (58) Employees' Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs printed your Tibetan molecular structure formula MW MS MP · Activity level 2 -14 Frost NI. Χ 332,40575 333 212-214 A 2-15 • People. 300,33564 301 214-216 B 2-16 'Crowd in. · 361,24124 362 237-239 A 2-17 .XX: Ν 人 0 Τ0 351,23527 352 234-235 A -60- This paper size applies to China Standard (CNS) A4 (210x297 mm) Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs, 200404052 A7 B7 V. Description of Invention (59)

實你贼分子結構式 MW MS ΜΡ 活性等級 2-18 XX>v Λ Χό 296,3723 297 198-200 Β 2-19 'N人。 χό 324,42648 325 186-188 A 2-20 Λ Χό 374,44339 375 188-190 A 2-21 π .χτ、 Λο 325,41406 326 206-207 D -61- 本紙張尺度適用中國國家標準(CNS)A4規格（210x297公釐）Real thief Molecular structure MW MS MP Activity level 2-18 XX > v Λ Χ 296,3723 297 198-200 Β 2-19 'N people. χό 324,42648 325 186-188 A 2-20 Λ χ 374,44339 375 188-190 A 2-21 π .χτ, Λο 325,41406 326 206-207 D -61- The paper size applies to the Chinese National Standard (CNS ) A4 size (210x297 mm)

200404052 經濟部智慧財產局員工消費合作社印製 A7 B7 五、發明說明（6〇 ) 實分分子結構式 MW - MS ΜΡ 活性等級 2-22 Χό 296,3723 297 198-200 Β 2-23 Χό 310,39939 311 224-226 Β 2-24 Χό 310,39939 311 194-196 Β 2-26 χχχ χό 310,39939 311 230-232 Α ^ -62- 本紙張尺度適用中國國家標準(CNS)A4規格（210x297公釐） 200404052 經濟部智慧財產局員工消費合作社印製 A7 B7 五、發明說明（61) 實命臟分子結構式 MW MS ΜΡ 活性等級 2-27 :Γ0 χό 314,36273 315 184-187 Β 2-28 Χ9 314,36273 315 ι 193-194 Β 2-29 χα 314,36273 315 218-221 A 2-30 χό χό 330,81733 331 213-215 巳 -63- 本紙張尺度適用中國國家標準(CNS)A4規格（210x297公釐） 200404052 A7B7 五、發明說明（62 ) 經濟部智慧財產局員工消費合作社印製200404052 A7 B7 printed by the Consumer Cooperative of Intellectual Property Bureau of the Ministry of Economic Affairs 5. Description of the invention (60) Actual molecular structure formula MW-MS MP Activity level 2-22 Ⅹ 296,3723 297 198-200 Β 2-23 Χ310, 39939 311 224-226 Β 2-24 Χ310,39939 311 194-196 Β 2-26 χχχ χό 310,39939 311 230-232 Α ^ -62- This paper size applies to China National Standard (CNS) A4 (210x297) (B) 200404052 A7 B7 printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs 5. Description of the invention (61) Molecular formula of MW MS LP Activity level 2-27: Γ0 χό 314,36273 315 184-187 Β 2-28 Χ9 314,36273 315 ι 193-194 Β 2-29 χα 314,36273 315 218-221 A 2-30 χό χό 330,81733 331 213-215 巳 -63- This paper size applies to China National Standard (CNS) A4 (210x297 mm) 200404052 A7B7 V. Description of the Invention (62) Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs

實分臟分子結構式 MW MS MP 活性等級 2-31 :χα? 326,39879 327 209-211 B 2-32 -Ν人0 ηοό6 310,39939 311 161-163 C 2-33 Ν 八 CH^ ' A. χό 234,3.0061 ； 235 216-217 D 2-34 NI人0 ΗΟχώ 282,34521 283 198-199 C -64- 本紙張尺度適用中國國家標準(CNS)A4規格（210 X 297公釐） 200404052 A7 B7 五、發明說明（63 ) 經濟部智慧財產局員工消費合作社印製Divided dirty molecular structure MW MS MP Activity grade 2-31: χα? 326,39879 327 209-211 B 2-32 -N human 0 ηοό 6 310,39939 311 161-163 C 2-33 Ν 八 CH ^ 'A χ 234,3.0061; 235 216-217 D 2-34 NI person 0 ΗΟχώ 282,34521 283 198-199 C -64- This paper size applies to China National Standard (CNS) A4 (210 X 297 mm) 200404052 A7 B7 V. Invention Description (63) Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs

實命織分子結構式 MW MS ΜΡ 活性等級 2-35 人。丨 N \〇 316,79024 317 197-199 Β 2-36 XC Λ Χό 330,81733 331 · >180Ζ A 2-37 Λ 入. χό 342,39819 343 >150Ζ A 2-38 F 巳Γ 463,68465 464 234-235 A 2-39 1 η If Η〇Χ^3 ch3 398,81 399 219-220 A -65- 本紙張尺度適用中國國家標準(CNS)A4規格（210x297公釐） 200404052 A7 ___B7 五、發明說明（64 )Real life weaving molecular structure MW MS MP activity level 2-35 people.丨 N \ 〇316,79024 317 197-199 Β 2-36 XC Λ Χ 330,81733 331 · > 180Z A 2-37 Λ .. χό 342,39819 343 > 150Z A 2-38 F 巳 Γ 463, 68465 464 234-235 A 2-39 1 η If Η〇Χ ^ 3 ch3 398,81 399 219-220 A -65- This paper size applies to China National Standard (CNS) A4 (210x297 mm) 200404052 A7 ___B7 5 Description of the invention (64)

實分赚分子結構式 MW MS MP 等級 2-40 爲 h3c、入 ρ F Χό 398,81571 399 136-137 巳 2-41 -t0Η’ 398,81571 399 213 B % 經濟部智慧財產局員工消費合作社印製 10 實例3-1 N-(4-氯·3-(三氟曱基）苯基)-N’-(7-羥基-5,6,7,8-四氫小萘基) 脲對掌性對映異構物此實例依據一般方法G進行。 15 於室溫下，在含對掌性8-胺基-1，2,3,4-四氫-萘-2-酚對映異構物（33.0mg，0.202 mmol)之 1，4-二畤烷(3.0 mL)溶液中添加異氰酸4-氯-3-三氟-甲基-苯酯（44.8 mg，0.202 mmol)。混合物攪拌16小時，然後添加二異丙醚與己烷。Real points earning molecular structure formula MW MS MP grade 2-40 is h3c, ρ F Χ 398,81571 399 136-137 巳 2-41 -t0Η '398,81571 399 213 B% Printed by the Consumers ’Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs Preparation 10 Example 3-1 N- (4-chloro · 3- (trifluorofluorenyl) phenyl) -N '-(7-hydroxy-5,6,7,8-tetrahydrosmallnaphthyl) urea This example is carried out according to General Procedure G. 15 At room temperature, in the 1,4-bis containing 8-amino-1,2,3,4-tetrahydro-naphthalene-2-phenol enantiomer (33.0 mg, 0.202 mmol) To the solution of pinane (3.0 mL) was added 4-chloro-3-trifluoro-methyl-phenyl isocyanate (44.8 mg, 0.202 mmol). The mixture was stirred for 16 hours, and then diisopropyl ether and hexane were added.

過濾沉澱及乾燥，產生對掌性N-(4-氯-3-(三氟曱基)-苯 20基）-N’-(7-羥基-W，8·四氩小萘基）脲（54.0 mg，收率69 %)。採用ChimlCel 0D管柱（15 %異丙醇之己炫滚液為、玄離液，以ΙπΛ/分鐘溶離)測定對映異構性超量(％ee)f / 分子量：384.8 MS (M+H): 384 25 mp:227-228〇C -66-The precipitate was filtered and dried to produce palmitic N- (4-chloro-3- (trifluorofluorenyl) -benzene 20-yl) -N '-(7-hydroxy-W, 8 · tetra-arginylnaphthyl) urea ( 54.0 mg, yield 69%). Enantiomeric excess (% ee) f / molecular weight: 384.8 MS (M + H) was measured using a ChimlCel 0D column (15% isopropyl alcohol in hexanes solution, dissociation solution, dissociation at 1πΛ / min). ): 384 25 mp: 227-228〇C -66-

200404052 A7 B7 五、發明說明（65) 活體外活性等級：A 實例4-1 N-(7-經基-5,6,7,8-四鼠-茶-1-基)-N’-(4-二說甲氧基-苯甲基)_ 5 脲〇200404052 A7 B7 V. Description of the invention (65) Activity level in vitro: A Example 4-1 N- (7-Cyclo-5,6,7,8-Tetramus-tea-1-yl) -N '-( 4-bis-methoxy-benzyl) -5 urea.

經濟部智慧財產局員工消費合作社印製 10 此實例依據一般方法C進行。取含7-羥基-5,6,7,8_四氫·萘小基)-胺甲酸苯酯（30.0mg， 0.11 mmol)與4-三氟曱氧基-苯曱基胺(21.3 mg，0· 11 mmol) 之DMSO(1.0 ml)混合物於100°C下攪拌17小時。反應混 15 合物冷卻至室溫，加水。過濾沉澱，以水與乙腈依序洗滌，得到N-(7-羥基-5,6,7,8-四氫-萘小基)-N’-(4-三氟曱氧基-苯曱基)-脲(6.70mg，收率17°/〇)。 lU NMR (DMSO-d6) δ 1.54-1.65 (m? 1H)，1.81-1.92 (m，lH)，2.25-2.38 (m，1H)，2.68-2.88 (m，3H)，3.86-3.98 (m， 20 1H)，4.32 (d5 J= 6·0 Hz，2H)，4.85 (d，J=4.1 Ηζ，1Η)，6·72 (d， J= 7.5 Hz，lH)，6.98 (t，J= 7·5 Hz，1H)，7.06 (t，J=6.0Hz，1H)， 7.34(d，J= 8.3 Hz，2H)，7.43 (d，J= 8·3 Hz，2H)，7.63 (d，J= 7·5 Hz，1H)，7.5 (s，1H) 〇分子量：380.36 25 MS (M+H): 381 -67- 本紙張尺度適用中國國家標準(CNS)A4規格（210x297公釐） 200404052 A7 ______B7Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs 10 This example is based on General Method C. Take 7-hydroxy-5,6,7,8_tetrahydro · naphthalene small group) -phenyl carbamate (30.0mg, 0.11 mmol) and 4-trifluorofluorenyloxy-phenylfluorenylamine (21.3 mg, A mixture of 0.11 mmol) of DMSO (1.0 ml) was stirred at 100 ° C for 17 hours. The reaction mixture was cooled to room temperature and water was added. The precipitate was filtered and washed sequentially with water and acetonitrile to obtain N- (7-hydroxy-5,6,7,8-tetrahydro-naphthalene small group) -N '-(4-trifluorofluorenyloxy-phenylfluorenyl group. ) -Urea (6.70 mg, yield 17 ° / 0). 1U NMR (DMSO-d6) δ 1.54-1.65 (m? 1H), 1.81-1.92 (m, lH), 2.25-2.38 (m, 1H), 2.68-2.88 (m, 3H), 3.86-3.98 (m, 20 1H), 4.32 (d5 J = 6.0 Hz, 2H), 4.85 (d, J = 4.1 Ηζ, 1Η), 6.72 (d, J = 7.5 Hz, 1H), 6.98 (t, J = 7 5 Hz, 1H), 7.06 (t, J = 6.0 Hz, 1H), 7.34 (d, J = 8.3 Hz, 2H), 7.43 (d, J = 8.3 Hz, 2H), 7.63 (d, J = 7.5 Hz, 1H), 7.5 (s, 1H) 〇 Molecular weight: 380.36 25 MS (M + H): 381 -67- This paper size applies to China National Standard (CNS) A4 (210x297 mm) 200404052 A7 ______B7

五、發明說明（66) mp:213〇C 活體外活性等級：A 實例4-2 5 N-{(R)-7-羥基-5,6,7,8-四氫-萘小基}七，_(4_三氟甲氧基-苯甲基)-脲V. Description of the invention (66) mp: 213 ° C Activity level in vitro: A Example 4-2 5 N-{(R) -7-hydroxy-5,6,7,8-tetrahydro-naphthalene small group} , _ (4_trifluoromethoxy-benzyl) -urea

此實例依據一般方法C進行。取含（R)-7-羥基_5,6,7,8-四氫-萘小基）_胺甲酸苯酯 (147.3 mg，0.52 mmol)與夂三氟甲氧基‘苯甲基胺（99·4 mg，0.52mmol)之 DMSO (1·5 mi)混合物於 i5〇°c 下擾拌 1·5 經濟部智慧財產局員工消費合作社印製 15小時。反應混合物冷卻至室溫，添加乙酸乙酯與水。萃取之有機層經水與鹽水依序洗滌，經硫酸鈉脫水，過濾及減壓濃縮。所得殘質與二氯甲烷及己烷研磨，得到N-{(R)-7-羥基_5,6,7,8_四氫·萘小基}->1，-(4-三氟甲氧基-苯甲基)-脲 (168.0 mg，收率 85°/。）。 20 ^NMR (DMSO-d6) 5 1.54-1.65 (m. 1H)? 1.8M.92 (m, 1H)5 2.25-2.38 (m，1H)，2.68-2.88 (m，3H)，3.86-3.98 (m，1H)，4.32 (d，J= 6.0 Hz，2H)，4.85 (d· J= 4·1 Hz，lH)，6.72 (d，J =7.5 Hz， 1H)· 6.98 (t，J= 7.5 Hz，1H)，7.06 (t，J= 6·0 Hz，1H)，7.34(d， J=8.3 Hz，2H)，7.43 (d，J= 8.3 Hz，2H)，7.63 (d，7.5 Hz， 25 1H)，7.5 (s，1H)。 -68- 本紙張尺度適用中國國家標準(CNS)A4規格（210x297公釐） 200404052 A7 B7 五、發明說明（67 )This example is performed according to General Method C. Take (R) -7-hydroxy_5,6,7,8-tetrahydro-naphthalene small group) phenyl carbamate (147.3 mg, 0.52 mmol) and fluorene trifluoromethoxy 'benzylamine ( A mixture of 99.4 mg, 0.52 mmol) of DMSO (1.5 mi) was stirred at 1.5 ° C for 1.5 hours and printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs for 15 hours. The reaction mixture was cooled to room temperature, and ethyl acetate and water were added. The extracted organic layer was washed sequentially with water and brine, dehydrated over sodium sulfate, filtered and concentrated under reduced pressure. The obtained residue was triturated with dichloromethane and hexane to obtain N-{(R) -7-hydroxy_5,6,7,8_tetrahydro · naphthalene small group}-> 1,-(4-trifluoro Methoxy-benzyl) -urea (168.0 mg, yield 85 ° /.). 20 ^ NMR (DMSO-d6) 5 1.54-1.65 (m. 1H)? 1.8M.92 (m, 1H) 5 2.25-2.38 (m, 1H), 2.68-2.88 (m, 3H), 3.86-3.98 ( m, 1H), 4.32 (d, J = 6.0 Hz, 2H), 4.85 (d · J = 4.1 Hz, 1H), 6.72 (d, J = 7.5 Hz, 1H), 6.98 (t, J = 7.5 Hz, 1H), 7.06 (t, J = 6.0 Hz, 1H), 7.34 (d, J = 8.3 Hz, 2H), 7.43 (d, J = 8.3 Hz, 2H), 7.63 (d, 7.5 Hz, 25 1H), 7.5 (s, 1H). -68- This paper size applies to China National Standard (CNS) A4 (210x297 mm) 200404052 A7 B7 V. Description of Invention (67)

分子量：380.36 MS (M+H): 381 活體外活性等級：A 對掌性 HPLC (ChiralCel AD 0·49 cm X 25 cm 管柱，正己 5 烷/乙醇=90 / 10,流速1.5 mL/分鐘），於17·7分鐘時檢測到R-異構物。實例4-3 N-{(S)-7-^i基-5,6,7,8-四氮-茶-1-基}_^^-(4-三氣曱氧基-苯 10 甲基)-脲 15 ΗΟ, 又 HN N ΗMolecular weight: 380.36 MS (M + H): 381 In vitro activity level: A pair of palm HPLC (ChiralCel AD 0.49 cm X 25 cm column, n-hexane 5 hexane / ethanol = 90/10, flow rate 1.5 mL / min) The R-isomer was detected at 17.7 minutes. Example 4-3 N-{(S) -7- ^ iyl-5,6,7,8-tetraaza-tea-1-yl} _ ^-(4-trifluorocarbyloxy-benzene 10 methyl ) -Urea 15 Η〇, HN N Η

Ό F 經濟部智慧財產局員工消費合作社印製此實例依據一般方法C進行。取含(S)-7-羥基-5,6,7,8-四氫-萘小基)-胺甲酸苯酯（85.0 mg，0.30 mmol)與4-三氟甲氧基-苯甲基胺（57.4 20 mg，0.30mmol)之 DMSO(1.0 ml)混合物於 150°C 下攪拌 1.5 小時。反應混合物冷卻至室溫，添加乙酸乙酯與水。萃取之有機層經水與鹽水依序洗滌，經硫酸鈉脫水，過濾與減壓濃縮。所得殘質與二氣甲烷及己烷研磨，得到N-{(S)-7-罗雙基-5,6,7,8-四鼠-秦-1-基}-]^’-(4-二氣甲氧基-苯曱基)-腺 -69- 本紙張尺度適用中國國家標準(CNS)A4規格（210x297公釐） 200404052 經濟部智慧財產局員工消費合作社印製 A7 B7 五、發明說明（68) (95.0 mg，收率 83 %)。 lH NMR (DMSO-d6) 5 1.54-1.65 (m，1H)，1.81-1.92 (m，1H)， 2.25-2.38 (m，1Η)，2·68-2·88 (m，3H)，3.86-3.98 (m，1H)，4.32 (d，J= 6.0 Hz，2H)，4.85 (d，J=4.1 Hz，lH)，6.72 (d，J= 7.5 Hz， 5 1H)，6.98 (t，J= 7.5 Hz，1H)，7.06 (t，JN 6.0 Hz，1H)，7.34(d，Ό F Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs This example is based on General Method C. Take (S) -7-hydroxy-5,6,7,8-tetrahydro-naphthalene small group) -phenyl carbamate (85.0 mg, 0.30 mmol) and 4-trifluoromethoxy-benzylamine (57.4 20 mg, 0.30 mmol) in DMSO (1.0 ml) was stirred at 150 ° C for 1.5 hours. The reaction mixture was cooled to room temperature, and ethyl acetate and water were added. The extracted organic layer was washed sequentially with water and brine, dehydrated over sodium sulfate, filtered and concentrated under reduced pressure. The obtained residue was triturated with digas methane and hexane to obtain N-{(S) -7-rosediyl-5,6,7,8-tetramus-qin-1-yl}-] ^ '-(4-di Gas Methoxy-Phenyl) -Gland-69- This paper size applies to Chinese National Standard (CNS) A4 (210x297 mm) 200404052 Printed by the Consumers ’Cooperative of Intellectual Property Bureau of the Ministry of Economic Affairs A7 B7 V. Invention Description (68 ) (95.0 mg, yield 83%). lH NMR (DMSO-d6) 5 1.54-1.65 (m, 1H), 1.81-1.92 (m, 1H), 2.25-2.38 (m, 1Η), 2.68-2 · 88 (m, 3H), 3.86- 3.98 (m, 1H), 4.32 (d, J = 6.0 Hz, 2H), 4.85 (d, J = 4.1 Hz, 1H), 6.72 (d, J = 7.5 Hz, 5 1H), 6.98 (t, J = 7.5 Hz, 1H), 7.06 (t, JN 6.0 Hz, 1H), 7.34 (d,

J= 8.3 Hz，2H)，7.43 (d，J= 8.3 Hz，2H)，7.63 (d，J= 7.5 Hz， 1H)，7.5 (s，1H) 〇分子量：380.36 MS(M+H):381 10 活體外活性等級：A 對掌性 HPLC(ChiralCel AD 0.49 cm x25 cm 管柱，正己烷 /乙醇90 / 10，流速1.5 mL/分鐘)於13·2分鐘時檢測到S-異構物。 15 實例4-4 N-{(R)-7-羥基-5,6,7,8-四氫-萘小基}*^’-(4-三氟曱基-苯甲基)-脲 20 25J = 8.3 Hz, 2H), 7.43 (d, J = 8.3 Hz, 2H), 7.63 (d, J = 7.5 Hz, 1H), 7.5 (s, 1H). Molecular weight: 380.36 MS (M + H): 381 10 In vitro activity level: A- palm HPLC (ChiralCel AD 0.49 cm x 25 cm column, n-hexane / ethanol 90/10, flow rate 1.5 mL / min) S-isomers were detected at 13.2 minutes. 15 Example 4-4 N-((R) -7-hydroxy-5,6,7,8-tetrahydro-naphthalene small group) * ^ '-(4-trifluorofluorenyl-benzyl) -urea 20 25

此實例依據一般方法C進行。取含（R)-7-羥基-5,6,7,8-四氫-萘小基）-胺甲酸苯酯 (150.0mg，0.53 mmol)與 4-三氟曱基-苯甲基胺 -70- 本紙張尺度適用中國國家標準(CNS)A4規格（210 X 297公釐） 200404052 A7 B7 五、發明說明（69) (92.7mg，〇.53mmol)之 DMSO(2.0 ml)混合物於 1〇〇。〇下攪拌 l. 5小時。反應混合物冷卻至室溫，添加乙酸乙酯與水。萃取之有機層經水與鹽水依序洗滌，經硫酸鈉脫水，過濾與減壓濃縮。所得殘質與二氯曱烷及己烷研磨，得到N- 5 {(R)-7-羥基-5,6,7,8-四氫-萘小基}-^-(4-三氟甲基-苯甲基)_ 脲（156mg，收率 81。/〇)。 iHNMR (DMS0-d6) 5 1.58-1.59 (m，1Η)，1·85-1.86 (m，1H)， 2.33-2.85 (m，4Η)，3·91-3·92 (m，1Η)，4.39 (d，J= 5·7 Ηζ，2Η)， 4.84 (d，J= 4·1Ηζ，1H)，6.72 (d，J=7.25Hz，lH)，6.98(t，J= 10 7·9Ηζ，1Η)，7·12 (t, J= 6·0Ηζ，lH)，7.51-7.71(m，6H) 〇分子量·. 364.37 MS(M+H):366This example is performed according to General Method C. Take (R) -7-hydroxy-5,6,7,8-tetrahydro-naphthalene small group) -phenyl carbamate (150.0mg, 0.53 mmol) and 4-trifluorofluorenyl-benzylamine- 70- This paper size is in accordance with Chinese National Standard (CNS) A4 (210 X 297 mm) 200404052 A7 B7 V. Description of the invention (69) (92.7mg, 0.53mmol) DMSO (2.0 ml) mixture in 100% . 〇下 stirred for 1.5 hours. The reaction mixture was cooled to room temperature, and ethyl acetate and water were added. The extracted organic layer was washed sequentially with water and brine, dehydrated over sodium sulfate, filtered and concentrated under reduced pressure. The obtained residue was triturated with dichloromethane and hexane to obtain N-5 {(R) -7-hydroxy-5,6,7,8-tetrahydro-naphthalene small group}-^-(4-trifluoromethyl -Benzyl) -urea (156 mg, yield 81%). iHNMR (DMS0-d6) 5 1.58-1.59 (m, 1Η), 1.85-1.86 (m, 1H), 2.33-2.85 (m, 4Η), 3.91-3 · 92 (m, 1Η), 4.39 (d, J = 5 · 7 Ηζ, 2Η), 4.84 (d, J = 4 · 1Ηζ, 1H), 6.72 (d, J = 7.25Hz, 1H), 6.98 (t, J = 10 7 · 9Ηζ, 1Η ), 7.12 (t, J = 6.00 ζ, 1H), 7.51-7.71 (m, 6H). Molecular weight. 364.37 MS (M + H): 366

m. p.:204.3°Cm.p.:204.3°C

活體外活性等級：A 15 對掌性 HPLC (ChiralCel AD 0·49 cm x25 cm 管柱，正己烧 /乙醇90 / 10，流速1.5 mL/分鐘)於16.2分鐘時檢測到異構物。實例4-5 經濟部智慧財產局員工消費合作社印製 20 义{(3)-7-經基-5,6,7,8-四氫-萘-1-基}-]^’-(4-三氟曱基-苯甲基)-脲In vitro activity level: A 15 pair palm HPLC (ChiralCel AD 0.49 cm x 25 cm column, n-hexane / ethanol 90/10, flow rate 1.5 mL / min) wasomers were detected at 16.2 minutes. Example 4-5 Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs of the People's Republic of China {(3) -7-Jingji-5,6,7,8-tetrahydro-naphthalene-1-yl}-] ^ '-(4 -Trifluorofluorenyl-benzyl) -urea

-71- 本紙張尺度適用中國國家標準(CNS)A4規格（210x297公釐） 200404052 Α7 Β7 五、發明說明（70) 經濟部智慧財產局員工消費合作社印製此實例依據一般方法C進行。取含（S)-7-羥基-5,6,7,8-四氫-萘小基）-胺甲酸笨酉旨 (100.0mg，0.35 mmol)與4-三氟甲基·苯甲基胺 (61.8mg，〇.35mmol)之 DMSO(1.5ml)混合物於 l〇〇°C 下攪拌 1.5小時。反應混合物冷卻至室溫，添加乙酸乙酯與水。萃取之有機層經水與鹽水依序洗務，經硫酸納脫水，過淚與減壓濃縮。所得殘質與二氯曱烷及二異丙醚研磨，得到义{(3)-7-羥基-5,6,7,8-四氫-萘小基}-沖-(4-三氟甲基、笨甲基)-脲（109mg，收率 85%)。 !H NMR (DMSO-d6) δ 1.58-1.59 (m5 1H)?1.85-1.86 (m5 2.33-2.85 (m，4Η)，3·91-3·92 (m，1H)，4.39 (d，J= 5.7 Hz，2H) 4.84 (d，J= 4·1Ηζ，1H)，6.72 (d，J=7.25Hz，lH)，6.98(t，了二 7·9Ηζ，1Η)，7·12 (t，J= 6·0Ηζ，lH)，7.51-7.71(m，6H)。分子量：364.37 15 MS(M+H):366 活體外活性等級：A 對掌性 HPLC(ChiralCelAD0.49cmx25cm 管柱，正己户 /乙醇90 / 10，流速1·5 mL/分鐘)於11·7分鐘時檢測到^ 異構物。 > 5 10 20 類似上述實例4-1、4-2、4-3、4-4與4-5之方法，成實例4-6至4-54 合 -72- 本纸張尺度適用中國國家標準(CNS)A4規格（210x297公釐） 200404052 A7 B7 經濟部智慧財產局員工消費合作社印製五、發明說明（7i) 表2-71- This paper size is in accordance with Chinese National Standard (CNS) A4 (210x297 mm) 200404052 Α7 Β7 V. Description of Invention (70) Printed by the Consumers' Cooperative of Intellectual Property Bureau of the Ministry of Economic Affairs This example is based on General Method C. Take (S) -7-hydroxy-5,6,7,8-tetrahydro-naphthalene small group) -carbamic acid (100.0mg, 0.35 mmol) and 4-trifluoromethyl · benzylamine A mixture of (61.8 mg, 0.35 mmol) in DMSO (1.5 ml) was stirred at 100 ° C for 1.5 hours. The reaction mixture was cooled to room temperature, and ethyl acetate and water were added. The extracted organic layer was sequentially washed with water and brine, dehydrated with sodium sulfate, and concentrated under reduced pressure. The obtained residue was triturated with dichloromethane and diisopropyl ether to obtain the meaning {(3) -7-hydroxy-5,6,7,8-tetrahydro-naphthalene small group} -Chong- (4-trifluoromethyl Methyl, stupid methyl) -urea (109 mg, yield 85%). ! H NMR (DMSO-d6) δ 1.58-1.59 (m5 1H)? 1.85-1.86 (m5 2.33-2.85 (m, 4Η)), 3 · 91-3 · 92 (m, 1H), 4.39 (d, J = 5.7 Hz, 2H) 4.84 (d, J = 4 · 1Ηζ, 1H), 6.72 (d, J = 7.25Hz, 1H), 6.98 (t, 7 · 9Ηζ, 1Η), 7 · 12 (t, J = 6. 0Ηζ, lH), 7.51-7.71 (m, 6H). Molecular weight: 364.37 15 MS (M + H): 366 In vitro activity grade: A pair of palm HPLC (ChiralCelAD 0.49cmx25cm column, hexane / ethanol 90/10, flow rate 1.5 mL / min) ^ isomers were detected at 11.7 minutes. &Gt; 5 10 20 Similar to the above examples 4-1, 4-2, 4-3, 4-4 and 4 The method of -5 is an example of 4-6 to 4-54. He-72- This paper size applies to China National Standard (CNS) A4 (210x297 mm) 200404052 A7 B7 Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs 、 Explanation of invention (7i) Table 2

實仔麟分子結構式 MW MS (M+H) MP 活性等級 4-6 XO χό 296,3723 297 198-200 B 4-7 rox)6 375,26833 376 220.5-222 A 4-8 F F niF OH 364,37068 365 186-187 A 4-9 a OH 330,81733 331 235 Z A 4-10 χό 364,37068 365 169,9 A -73- 本紙張尺度適用中國國家標準(CNS)A4規格（210 x 297公釐） 200404052 A7 B7 經濟部智慧財產局員工消費合作社印製Molecular formula MW MS (M + H) MP Activity level 4-6 XO χ, 296,3723 297 198-200 B 4-7 rox) 6 375,26833 376 220.5-222 A 4-8 FF niF OH 364 , 37068 365 186-187 A 4-9 a OH 330,81733 331 235 ZA 4-10 χ 364,37068 365 169,9 A -73- This paper size applies to China National Standard (CNS) A4 (210 x 297 male) (2004) 200404052 A7 B7 Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs

五、發明說明（72 ) 4-11 χύ χό 326,39879 327 196 Β 4-12 χα: χό 332,35316 333 193,4 A 4-13 χό . 326,39879 327 171,3 Β 4-14 χα。 η°ό6 330,81733 331 188,7 A 4-15 χά。 Χό 365,26236 366 212,7 A 4-16 Ηχώ 352,48066 353 199,9 A -74- 本紙張尺度適用中國國家標準(CNS)A4規格（210x297公釐） 200404052 A7 經濟部智慧財產局員工消費合作社印製V. Description of the invention (72) 4-11 χύ χό 326,39879 327 196 Β 4-12 χα: χό 332,35316 333 193,4 A 4-13 χό. 326,39879 327 171,3 Β 4-14 χα. η ° ό 6 330,81733 331 188,7 A 4-15 χά. 365,26236 366 212,7 A 4-16 ώχώ 352,48066 353 199,9 A -74- This paper size applies to China National Standard (CNS) A4 specification (210x297 mm) 200404052 A7 Intellectual Property Bureau, Ministry of Economic Affairs, employee consumption Printed by a cooperative

五、發明說明（73 ) 4-17 χό 380,37008 381 213 A 4-18 X€C Χό 365,26236 366 201,4 A 4-19 χί Χό . 364,37068 365 218,6 A 4-20 〇^. Τό 356,42528 357 212 Β 4-21 Λ?0 Χύ 375,26833 376 206,4 A 4-22 XXl〇. Ν \〇 Υ、ch3 χό、 354,40934 355 210,9 A -75- 本紙張尺度適用中國國家標準(CNS)A4規格（210 x 297公釐） 200404052 A7 B7 五、發明說明（74 ) 經濟部智慧財產局員工消費合作社印製V. Description of the invention (73) 4-17 χό 380,37008 381 213 A 4-18 X € C Χό 365,26236 366 201,4 A 4-19 χί IX. 364,37068 365 218,6 A 4-20 〇 ^. Τό 356,42528 357 212 Β 4-21 Λ? 0 Χύ 375,26833 376 206,4 A 4-22 XXl〇. Ν \ 〇Υ, ch3 χό, 354,40934 355 210,9 A -75- present Paper size applies to China National Standard (CNS) A4 (210 x 297 mm) 200404052 A7 B7 V. Description of Invention (74) Printed by the Consumer Cooperative of Intellectual Property Bureau of the Ministry of Economic Affairs

4-23 0^ ^ -Ν人0 Χό : 386,45177 387 175,4 C 4-24 ΗΌ0 375,26833 376 164,2 A 4-25 χα,'。 χό八 341,36983 342 216,3 A 4-26 嘗十 432,36906 433 200,3 A 4-27 Λ?α：" Η〇ν^Λ, 、 ΧΌ 356,42528 357 219,7 C -76- 本紙張尺度適用中國國家標準(CNS)A4規格（210 X 297公釐） 200404052 A7 五、發明說明（75 ) 經濟部智慧財產局員工消費合作社印製4-23 0 ^ ^ -Ν 人 0 Χ: 386,45177 387 175,4 C 4-24 ΗΌ0 375,26833 376 164,2 A 4-25 χα, '. X 341,36983 342 216,3 A 4-26 Taste ten 432,36906 433 200,3 A 4-27 Λ? α: " Η〇ν ^ Λ,, ΧΌ 356,42528 357 219,7 C -76 -This paper size is applicable to China National Standard (CNS) A4 (210 X 297 mm) 200404052 A7 V. Description of Invention (75) Printed by the Consumer Cooperative of Intellectual Property Bureau of the Ministry of Economic Affairs

4-28 N人0 Ηχό 332,35316 333 140,2 C 4-29 χό 380,37008 381 149 A 4-30 Χό .。 340,38225 341 278,5 C 4-31 狀 χό 311,38697 312 223 C 4-32 Χύ Χό 311,38697 312 132,5 C -77- 本紙張尺度適用中國國家標準(CNS)A4規格（210x297公釐） 200404052 A7 B7 經濟部智慧財產局員工消費合作社印製4-28 N people 0 Ηχό 332,35316 333 140,2 C 4-29 χό 380,37008 381 149 A 4-30 Χό. 340,38225 341 278,5 C 4-31 Status 311,38697 312 223 C 4-32 Χύ Χό 311,38697 312 132,5 C -77- This paper size applies to China National Standard (CNS) A4 (210x297) (2004) 200404052 A7 B7 Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs

五、發明說明（76 ) 4-33 Λ χό 368,43643 369 . 209,5 Β .4-34 Ηχύ 339,44115 340 197.7-199.5 A 4-35 •〇 Ν 人 ^Όό. Γ F 398,81571 399 187,5 A 4-36 Λ^σα τό. 344,84442' 345 >200 A 4-37 人-η τό W 382,36111 383 174 A 4-38 ΗΝ人0 Ηχώ 388,47048 389 181-183 A -78- 本紙張尺度適用中國國家標準(CNS)A4規格（210 X 297公釐） 200404052 A7 B7 五、發明說明（77 ) 經濟部智慧財產局員工消費合作社印製V. Description of the invention (76) 4-33 Λ χό 368,43643 369. 209,5 Β .4-34 Ηχύ 339,44115 340 197.7-199.5 A 4-35 • 〇Ν person ^ Όό. Γ F 398,81571 399 187,5 A 4-36 Λ ^ σα τό. 344,84442 '345 > 200 A 4-37 people-η τό W 382,36111 383 174 A 4-38 ΗΝ 人 0 Ηχώ 388,47048 389 181-183 A -78- This paper size is in accordance with Chinese National Standard (CNS) A4 (210 X 297 mm) 200404052 A7 B7 V. Invention Description (77) Printed by the Consumer Cooperative of Intellectual Property Bureau of the Ministry of Economic Affairs

4-39 ηΛο 408,88842 409 199-201 A 4-40 Ηχώ' 366,34299 367 198-200 A 4-41 • CH3 愈慧 328,38982 329 163-164 B 4-42 ch3 —、叙 ΗΧό 389,29542 389-391 174 A 4-43 0 j!〇 H01C0 372,47108 373 205-206 C -79- 本紙張尺度適用中國國家標準(CNS)A4規格（210 X 297公釐） 200404052 A7 B7 五、發明說明（7〇經濟部智慧財產局員工消費合作社印製 4-44 ΗΝ^Ο ΗΧό 358,87151 359 140-141 Β 4-45 χο>; 396,43468 397 209,1 A 4-46 η；ι^9 ηοό6' 346,43284 347 221,1 A 4-47 ΗΝ人〇 Η〇Ό0 321,38218 322 147分解 Β 4-48 ch3 ：xj〇 ηοό6 310,39939 311 169,6 Β -80- 本紙張尺度適用中國國家標準(CNS)A4規格（210 X 297公釐） 200404052 A7 B7 經濟部智慧財產局員工消費合作社印製4-39 ηΛο 408,88842 409 199-201 A 4-40 ώχώ '366,34299 367 198-200 A 4-41 • CH3 Yuhui 328,38982 329 163-164 B 4-42 ch3 —, Xu Xuan 389, 29542 389-391 174 A 4-43 0 j! 〇H01C0 372,47108 373 205-206 C -79- This paper size applies to China National Standard (CNS) A4 (210 X 297 mm) 200404052 A7 B7 V. Invention Explanation (printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs 4-44 ΗΝ ^ Ο ΗΧ 358,87151 359 140-141 Β 4-45 χο >; 396,43468 397 209,1 A 4-46 η; ι ^ 9 ηοό6 '346,43284 347 221,1 A 4-47 人 Ν 人〇Η〇Ό0 321,38218 322 147 Decomposition Β 4-48 ch3: xj〇ηοό 6 310,39939 311 169,6 Β -80- The paper size is applicable China National Standard (CNS) A4 (210 X 297 mm) 200404052 A7 B7 Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs

五、發明說明（79 ) 4-49 册 χό 360,45993 361 137,4 A 4-50 〇 ΗΝ人Ν八〇 ϋ。 375,44977 376 >200分解 C 4-51 •〇 ΗΝ 人 hYyV W 447,50486 448 159 A 4-52 -〇 HN人. H〇rrSH · Vyff VJ- CIH 483,96583 448 83 A 4-53 i3"cl ηΛο ΗΧώ 344,84442 345 173,9 A -81- 本紙張尺度適用中國國家標準(CNS)A4規格（210x297公釐） 200404052 A7 B7 五、發明說明（8〇 )V. Description of the Invention (79) 4-49 Book 360,45993 361 137,4 A 4-50 〇 ΝΝΝΝ80. 375,44977 376 > 200 decomposition C 4-51 • 〇ΗΝ human hYyV W 447,50486 448 159 A 4-52 -〇HN human. H〇rrSH · Vyff VJ- CIH 483,96583 448 83 A 4-53 i3 " cl ηΛο ΗΧώ 344,84442 345 173,9 A -81- This paper size applies to Chinese National Standard (CNS) A4 (210x297 mm) 200404052 A7 B7 V. Description of the invention (80)

經濟部智慧財產局員工消費合作社印製本紙張尺度適用中國國家標準(CNS)A4規格（210x297公釐） 200404052 Α7 Β7Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs This paper is sized for the Chinese National Standard (CNS) A4 (210x297 mm) 200404052 Α7 Β7

五、發明說明（81) 實例4-48V. Description of the Invention (81) Example 4-48

N-[(7R)_7_羥基-5,6,7,8-四氫小萘基]-Ν，_{2_[4_(三氟曱基) 苯基]-乙基}腺 5 HON-[(7R) _7_hydroxy-5,6,7,8-tetrahydrosmallnaphthyl] -N, _ {2_ [4_ (trifluorofluorenyl) phenyl] -ethyl} gland 5 HO

10 此實例依據一般方法C進行。取含7-羥基-5,6,7,8-四氫-萘小基）_胺曱酸苯酉旨 (100.0mg，0.35 mmol)與2_(4_三氟甲基-苯基）乙胺 (66.7mg，0.35mmol)之 DMSO(l.Oml)混合物於 6〇°c 下擾摔 3 小時。反應混合物冷卻至室溫，混合物分佈在乙酸乙醋與 15 水之間。有機層經硫酸鈉脫水，蒸發至乾。粗產物與乙鱗攪拌，過濾沉澱及真空乾燥，產生N-[(7R)-7-羥基-5,6,7,8-四氫氺萘基]-N，-{2-[4-(三氟曱基）苯基]乙基}脲（125 mg，收率 94 %)。經濟部智慧財產局員工消費合作社印製 ]ΗΝΜΚ (DMSO-d6)(5 1.45-1.68(m, 1H), 1.78-1.93 (m, 1H)? 20 2.29 (dd，1H)，2.65-2.93 (m，5H)，3.39 (dt，2Η)，3·80-4·00 (m， 1H)，4.88 (d，1H)，6.57 (t，1H)，6.70 (d，lH)，6·98 (t，1H)， 7.42-7.75 (m，6 H) 〇分子量：378.39 MS(M+H):379 -83- 本紙張尺度適用中國國家標準(CNS)A4規格（210 X 297公爱） 200404052 A7 B7 五、發明說明（82) 實例4-49 N-[(7R)-7-羥基-5,6,7,8-四氫小萘基]-Nf-{2-[4-(三氟甲氧基) 苯基]-乙基}脲10 This example is performed according to General Method C. Take 7-hydroxy-5,6,7,8-tetrahydro-naphthalene small group) amine amino acid benzoate (100.0mg, 0.35 mmol) and 2- (4-trifluoromethyl-phenyl) ethylamine (66.7 mg, 0.35 mmol) in a mixture of DMSO (1.0 ml) was stirred at 60 ° C for 3 hours. The reaction mixture was cooled to room temperature and the mixture was distributed between ethyl acetate and 15 water. The organic layer was dried over sodium sulfate and evaporated to dryness. The crude product was stirred with ethyl scale, and the precipitate was filtered and dried under vacuum to produce N-[(7R) -7-hydroxy-5,6,7,8-tetrahydronaphthyl] -N,-{2- [4- ( Trifluorofluorenyl) phenyl] ethyl} urea (125 mg, yield 94%). Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs] ΗNMK (DMSO-d6) (5 1.45-1.68 (m, 1H), 1.78-1.93 (m, 1H)? 20 2.29 (dd, 1H), 2.65-2.93 (m , 5H), 3.39 (dt, 2Η), 3.80-4 · 00 (m, 1H), 4.88 (d, 1H), 6.57 (t, 1H), 6.70 (d, 1H), 6.98 (t ， 1H), 7.42-7.75 (m, 6 H) 〇 Molecular weight: 378.39 MS (M + H): 379 -83- This paper size applies Chinese National Standard (CNS) A4 specification (210 X 297 public love) 200404052 A7 B7 V. Description of the invention (82) Example 4-49 N-[(7R) -7-hydroxy-5,6,7,8-tetrahydrosmallnaphthyl] -Nf- {2- [4- (trifluoromethoxy ) Phenyl) -ethyl} urea

〇\ CF3 10 此實例依據一般方法C進行。取含7-經基-5,6,7,8-四鼠-秦-1-基）-胺甲酸苯西旨 (100.0mg，0.35 mmol)與2-(4-三氟甲氧基-苯基）乙胺 (72.4mg，0.35mmol)之 DMSO(l.Oml)混合物於 60°C 下攪拌 2.5小時。反應混合物冷卻至室溫，混合物分佈在乙酸乙 15 酯與水之間。有機層經硫酸鈉脫水，蒸發至乾。粗產物與 ***攪拌，過濾沉澱及真空乾燥，產生N-[(7R)-7-羥基-5,6,7,8-四氫-1-蒸基]-N’-{2-[4_(三氟甲氧基）苯基]乙基}脈 (109 mg，收率 79 %)。經濟部智慧財產局員工消費合作社印製 iHNMR (DMSO-d6) 1.50-1.65 (m，1H)，1.80-1.91 (m，lH)， 20 2.30 (dd，1H)，2.60-2.88 (m，5H)，3·34 (dt，2H)，3.85-3.97 (m， 1H)， 4.81 (d， 1H)， 6.55 (t， 1H)， 6.70 (d，lH)， 6.98 (t，lH)，7.30(d，2Η)，7·38 (d，2H)，7.50 (s，lH)，7.59(d，1H)。分子量：394.39 MS(M+H):395 25 -84- 本紙張尺度適用中國國家標準(CNS)A4規格（210 X 297公釐） 200404052 A7 B7 經濟部智慧財產局員工消費合作社印製五、發明說明（83 ) 表3〇 \ CF3 10 This example was performed according to General Method C. Take 7-Cycyl-5,6,7,8-tetramurine-qin-1-yl) -carbamic acid benzoic acid (100.0mg, 0.35 mmol) and 2- (4-trifluoromethoxy-benzene A mixture of methyl) ethylamine (72.4 mg, 0.35 mmol) in DMSO (1.0 ml) was stirred at 60 ° C for 2.5 hours. The reaction mixture was cooled to room temperature, and the mixture was distributed between ethyl acetate and water. The organic layer was dried over sodium sulfate and evaporated to dryness. The crude product was stirred with diethyl ether, the precipitate was filtered and dried under vacuum to produce N-[(7R) -7-hydroxy-5,6,7,8-tetrahydro-1-dichloro] -N '-{2- [4_ ( Trifluoromethoxy) phenyl] ethyl} vein (109 mg, yield 79%). Printed by iHNMR (DMSO-d6) 1.50-1.65 (m, 1H), 1.80-1.91 (m, lH), 20 2.30 (dd, 1H), 2.60-2.88 (m, 5H) , 3.34 (dt, 2H), 3.85-3.97 (m, 1H), 4.81 (d, 1H), 6.55 (t, 1H), 6.70 (d, lH), 6.98 (t, lH), 7.30 (d , 2Η), 7.38 (d, 2H), 7.50 (s, 1H), 7.59 (d, 1H). Molecular weight: 394.39 MS (M + H): 395 25 -84- This paper size applies to China National Standard (CNS) A4 (210 X 297 mm) 200404052 A7 B7 Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs Explanation (83) Table 3

實作贼分子結構式 MW fyis (M+H) MP 活性等級 5-2 χό .F 300,336 301 c - 5-3 人众 Ηχώ 300,336 301 204-205 B 5-4 Χό， 361,241 362 196-197 B . 5-5 ΛΛ, Χό 361,241 362 A 5-6 Λ^) Χό q 296,372 297 223 C -85- 本紙張尺度適用中國國家標準(CNS)A4規格（210 X 297公釐） 200404052 A7 B7 五、發明說明（84 ) 經濟部智慧財產局員工消費合作社印製 5-7 人XT Τό 296,372 297 Β 5-8 N N 丫 χό ' 324,426 325 A 5-9 . H3V% λΧ?" χό ' 338,454 339 A 5-10 ΛΛ' Χό ό 374,443 375 194-195 A 5-11 λΑ〇 Ηχώ、f 366,343 367 203-204 .A 5-12 .，η3 人ώ/ 380,37 381 A -86- 本紙張尺度適用中國國家標準(CNS)A4規格（210x297公釐） 200404052 A7 B7 五、發明說明（85 ) 經濟部智慧財產局員工消費合作社印製The molecular structure formula of MW fyis (M + H) MP was implemented. The activity level was 5-2. F 300,336 301 c-5-3 People 300,336 301 204-205 B 5-4 X, 361,241 362 196-197 B. 5-5 ΛΛ, Χό 361,241 362 A 5-6 Λ ^) XX q 296,372 297 223 C -85- This paper size applies to China National Standard (CNS) A4 (210 X 297 mm) 200404052 A7 B7 V. Description of the invention (84) 5-7 people printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs XT 296,372 297 Β 5-8 NN λχ '324,426 325 A 5-9. H3V% λχ? &Quot; χό' 338,454 339 A 5-10 ΛΛ 'ό 374,443 375 194-195 A 5-11 λΑ〇Ηχώ, f 366,343 367 203-204 .A 5-12., Η3 person free / 380,37 381 A -86- This paper size applies Chinese national standards ( CNS) A4 specification (210x297 mm) 200404052 A7 B7 V. Description of invention (85) Printed by the Consumer Cooperative of Intellectual Property Bureau of the Ministry of Economic Affairs

5-13 A N^O Χό 408,242 409 226-228 A .5-14 χύ 326,399 327 >192Ζ .A 5-15 入 χό . 328,371 329 >82Ζ C 5-16 Ν人0 κοό6 328,436 329 >186Ζ Β 5-17 XC' Ν人0 ΗΧό 330,362 331 >185Ζ A -87- ，本紙張尺度適用中國國家標準(CNS)A4規格（210x297公釐） 200404052 經濟部智慧財產局員工消費合作社印製 A7 B7 五、發明說明（86 ) 5-18 N人0 Χό 342,398 343 203-212 Β 5-19 XX、 Ν人0 χό 346,817 347 >200Ζ A 5-20 XT N N人0 Ηχύ . 298,345 299 >202Ζ C 5-21 ch3 · Λ Χό 310,399 311 >223Ζ A 5-22 Νπ： Ν人0 ΗΧ0 310,399 311 >197Ζ A -88- ，本紙張尺度適用中國國家標準(CNS)A4規格（210x297公釐） 200404052 A7 B7 經濟部智慧財產局員工消費合作社印製五、發明說明（87 ) -89-5-13 AN ^ O Χό 408,242 409 226-228 A .5-14 χύ 326,399 327 > 192Z .A 5-15 χό. 328,371 329 > 82ZZ C 5-16 Ν 人 0 κοό6 328,436 329 > 186ZZ Β 5-17 XC 'Ν 人 0 ΗΧό 330,362 331 > 185Z A -87-, this paper size applies the Chinese National Standard (CNS) A4 specification (210x297 mm) 200404052 Printed by A7 B7 of the Consumer Cooperative of Intellectual Property Bureau of the Ministry of Economic Affairs Description of the invention (86) 5-18 N people 0 Χό 342,398 343 203-212 Β 5-19 XX, Ν person 0 χό 346,817 347 > 200Z A 5-20 XT NN people 0 Ηχύ. 298,345 299 > 202Z C 5 -21 ch3 · Λ Χ310,399 311 > 223Z A 5-22 Νπ: Ν 人 0 ΗΧ0 310,399 311 > 197Z A -88-, this paper size applies the Chinese National Standard (CNS) A4 specification (210x297 mm) 200404052 A7 B7 Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs V. Invention Description (87) -89-

5-23 入％ HOr0 310,399 311 >142Ζ A 5-24 Λ ηοχ)6 314,363 315 >197Ζ A 本紙張尺度適用中國國家標準(CNS)A4規格（210 X 297公釐） 200404052 A7 B7 五、發明說明（實例5-1 基-5,6,7,8-四鼠-奈-1-基)-N’-(4-二氣甲氧基-苯基)-脈5-23%% HOr0 310,399 311 > 142Z A 5-24 Λ ηοχ) 6 314,363 315 > 197Z A The paper size applies to China National Standard (CNS) A4 (210 X 297 mm) 200404052 A7 B7 V. Invention Description (Example 5-1 yl-5,6,7,8-tetramurine-naphthalen-1-yl) -N '-(4-diaminomethoxy-phenyl) -vein

此實例依據一般方法E進行。 10 取含 8-胺基-1，2,3,4-四氫-萘-2-紛(32.6 mg，0.20 mmol) 與(4-三氟曱氧基-苯基)-胺甲酸苯酯（59.5 mg，0.20 mmol)之 DMSO(1.0 ml)混合物於100°C下攪拌1.5小時。混合物減壓濃縮，然後經製備性HPLC純化，得到N-(7-羥基-5,6,7,8-四氮-茶-1-基)-N’_(4-二氟甲氧基-苯基)-腺 15 (15.5〇^，收率21%)。 1HNMR(DMSO-d6) (51.61 (m, ΙΗχΐ.87 (m? 1H)5 2.40 (m5 1H), 2.85 (m，2H)，3.96(m，1H), 4.88 (d，J= 4·2 Hz，1H)，6.80 (d，J= 7.2 Hz，1H)，7.05 (t，J= 7·2 Hz，1H)，7.28 (d，8.7 Hz，2H)，7·55 (d， 9.3 Hz，2H)，7.63 (d，J= 7·2 Hz，1H)，7.85 (s，lH)，9.24(s，1H)。經濟部智慧財產局員工消費合作社印製This example is performed according to General Method E. 10 Take 8-amino-1,2,3,4-tetrahydro-naphthalene-2-pentene (32.6 mg, 0.20 mmol) and (4-trifluorofluorenyloxy-phenyl) -carbamic acid phenyl ester ( A mixture of 59.5 mg, 0.20 mmol) of DMSO (1.0 ml) was stirred at 100 ° C for 1.5 hours. The mixture was concentrated under reduced pressure and then purified by preparative HPLC to give N- (7-hydroxy-5,6,7,8-tetraaza-tea-1-yl) -N '_ (4-difluoromethoxy- Phenyl) -gland 15 (15.5%, yield 21%). 1HNMR (DMSO-d6) (51.61 (m, ΙΗχΐ.87 (m? 1H) 5 2.40 (m5 1H), 2.85 (m, 2H), 3.96 (m, 1H), 4.88 (d, J = 4.2 Hz , 1H), 6.80 (d, J = 7.2 Hz, 1H), 7.05 (t, J = 7.2 Hz, 1H), 7.28 (d, 8.7 Hz, 2H), 7.55 (d, 9.3 Hz, 2H ), 7.63 (d, J = 7.2 Hz, 1H), 7.85 (s, 1H), 9.24 (s, 1H). Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs

20 分子量：366.34 MS(M+H):367 mp: 198-200〇C 活體外活性等級：A 類似上述實例5-1之方法，合成實例5-2至5-24。 25 圖式簡單說明無 -90- 本紙張尺度適用中國國家標準(CNS)A4規格（210x297公釐）20 Molecular weight: 366.34 MS (M + H): 367 mp: 198-200 ° C In vitro activity level: A Similar to the method of Example 5-1 above, Examples 5-2 to 5-24 were synthesized. 25 Schematic illustrations None -90- This paper size applies to China National Standard (CNS) A4 (210x297 mm)

Claims

200404052 A8 B8 C8 D8 六、申請專利範圍 1. 一種式(I)經基-四氫-萘脲衍生物異構型，或其鹽：〇其互變異構型或立體200404052 A8 B8 C8 D8 6. Scope of patent application 1. An acyl-tetrahydro-naphthyl urea derivative of formula (I) isomer, or its salt: 〇 tautomeric or stereo

z (I) 其中 X 代表烷基z (I) where X is alkyl

-R3 丫 i /R 一 R2 'R 計或線其中 Y代表一直接鍵結 R° 經濟部智慧財產局員工消費合作社印製 R 或 R R7 R4 R R1、R2與R3分別獨立代表氫、鹵素、經基、石肖基、魏基、胺基、Ci_6烧胺基、二(Ci_6烧基）胺基、C3_8環烷胺基、Cw烷氧羰基、苯基、苯甲 -91 - 本紙張尺度適用中國國家標準(CNS)A4規格（210 X 297公釐） 92214申請專利範圍 200404052 A8 B8 C8 D8 六經濟部智慧財產局員工消費合作社印製申請專利範圍基、續酸胺、Cl _6烧酿基、Cl-6烧酿胺基、胺曱醯基、Cw烷胺甲醯基、氰基、可視需要經氰基、Cw烷氧羰基或單-、二-或三鹵素取代之Ci_6 烷基、可視需要經單…二-或三i素取代之Ci_6 烷氧基、可視需要經鹵素或Cw烷基取代之苯氧基、或可視需要經單-、二-或三鹵素取代之Ci_6 烷硫基； R4、R5、R6、與R7分別獨立代表氫、Cm &基或苯基； Z1代表氫或Cw烷基；及 Z2代表氫、鹵素或Cw烷基。 2.根據申請專利範圍第1項之式(I)羥基-四氳-莕脲衍生物、其互變異構型或立體異構型、或其鹽，其中 X 代表-R3 y i / R-R2 'R meter or line where Y represents a direct bond R ° Printed by R or R R7 R4 R R1, R2 and R3 independently represent hydrogen, halogen, Jingji, Shixiaoji, Weiji, Amine, Ci_6Amine, Di (Ci_6Amine), C3_8Cycloalkylamino, Cw Alkoxycarbonyl, Phenyl, Benzo-91-This paper is applicable to China Standard (CNS) A4 specification (210 X 297 mm) 92214 Application for patent scope 200404052 A8 B8 C8 D8 Six employees of the Intellectual Property Bureau of the Ministry of Economic Affairs Consumer Cooperatives printed application scope for patents, continuous acid amines, Cl_6 brewing bases, Cl- 6Aromatic amino, amidino, Cw alkylaminomethyl, cyano, Ci_6 alkyl substituted with cyano, Cw alkoxycarbonyl, or mono-, di- or trihalogen, if necessary … Ci_6 alkoxy substituted by di- or tri-i, phenoxy substituted by halogen or Cw alkyl if necessary, or Ci_6 alkylthio substituted by mono-, di-, or tri-halogen if necessary; R4, R5 , R6, and R7 each independently represent hydrogen, Cm & or phenyl; Z1 represents hydrogen or Cw alkane ; And Z2 represents hydrogen, halogen or Cw alkyl. 2. A hydroxy-tetrahydrazone-urea urea derivative, a tautomeric or stereoisomeric form thereof, or a salt thereof according to item (1) of the scope of the patent application, where X represents

其中 Y代表一直接鍵結，或 R5 R4 -92 -Where Y represents a direct bond, or R5 R4 -92-

本紙張尺度適用中國國家標準(CNS)A4規格（210x297公釐） 200404052 六經濟部智慧財產局員工消費合作社印製 A8 B8 C8 D8 申請專利範圍 R1、R2、與R3分另，J獨立代表氫、鹵素、經基、硝基、魏基、胺基、Ci_6烧胺基、二(Ci_6烧基)胺基、C3_8環烷胺基、Cw烷氧羰基、苯基、苯甲基、續酸胺、Cl _6烧酿基、Cl 烧酿基胺基、胺甲醯基、Cw烷基胺甲醯基、氰基、可視需要經氰基、Ci_6烧氧幾基或單-、二-或三鹵素取代之Ci-6烷基、可視需要經單-、二-或三齒素取代之Cw烷氧基、可視需要經i素或Cm烷基取代之笨氧基、或可視需要經單-、二-或三鹵素取代之Ci_6烷硫基； R4與R5分別獨立代表氫或Cw烷基；且 Z1與Z2分別獨立代表氫。，·根據申請專利範圍第1項之式(I)羥基-四氫-萘脲衍生物、其互變異構型或立體異構型、或其鹽，其中 X 代表This paper size applies to the Chinese National Standard (CNS) A4 specification (210x297 mm) 200404052 Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs A8 B8 C8 D8 Patent application scopes R1, R2, and R3 In addition, J independently represents hydrogen, Halogen, triphenyl, nitro, weyl, amine, Ci-6 amine, bis (Ci_6) amine, C3_8 cycloalkylamino, Cw alkoxycarbonyl, phenyl, benzyl, diamine, Cl_6 alkynyl, Cl alkynyl amine, carbamoyl, Cw alkylaminomethyl, cyano, optionally substituted with cyano, Ci_6 alkoxy, or mono-, di-, or trihalogen Ci-6 alkyl, optionally substituted with mono-, di-, or tridentin, Cw alkoxy, optionally substituted with i- or Cm alkyl, or optionally, mono-, di- Or trihalo-substituted Ci-6 alkylthio; R4 and R5 each independently represent hydrogen or Cw alkyl; and Z1 and Z2 each independently represent hydrogen. , According to formula (I) of a hydroxy-tetrahydro-naphthyl urea derivative, its tautomeric or stereoisomeric form, or a salt thereof according to item 1 of the scope of the patent application, where X represents

•R3 、丫〆• R3, maid

，或其中 Y代表一直接鍵結，或 R5 R 93 - 本紙張尺度適用中國國家標準(CNS)A4規格（210x297公釐） 200404052 A8 B8 C8 D8 經濟部智慧財產局員工消費合作社印製 Λ 申請專利範圍 R1、R2、與R3分別獨立代表氫、鹵素、二（Cu烧基）胺基、C3_8環烷胺基、Cw烷氧羰基、可視需要經氰基、Cw烷氧羰基或單-、二-或三鹵素取代之Cu烷基、可視需要經單-、二·或三鹵素取代之Ck烧氧基、可視需要經鹵素或Ci_6 烷基取代之苯氧基、或可視需要經單-、二-或三鹵素取代之Ci_6烷硫基； R4與R5分別獨立代表氫；且 Z1與Z2分別獨立代表氫。 4.根據申請專利範圍第1項之式(I)羥基-四氫-萘脲衍生物、其互變異構型或立體異構型、或其鹽，其中 X 代表, Or where Y represents a direct bond, or R5 R 93-This paper size applies to the Chinese National Standard (CNS) A4 specification (210x297 mm) 200404052 A8 B8 C8 D8 Printed by the Employees ’Cooperative of Intellectual Property Bureau of the Ministry of Economic Affairs Λ Apply for a patent The ranges R1, R2, and R3 each independently represent hydrogen, halogen, di (Cu alkyl) amino, C3-8 cycloalkylamino, Cw alkoxycarbonyl, optionally through cyano, Cw alkoxycarbonyl, or mono-, di- Cu alkyl substituted by tri- or halogen, mono-, di-, or tri-halogen substituted alkoxy, optionally substituted by halogen or Ci-6 alkyl phenoxy, or mono-, di-, if required Or trihalo-substituted Ci-6 alkylthio; R4 and R5 each independently represent hydrogen; and Z1 and Z2 each independently represent hydrogen. 4. A hydroxy-tetrahydro-naphthyl urea derivative of formula (I), a tautomeric or stereoisomeric form thereof, or a salt thereof according to item 1 of the scope of the patent application, where X represents

其中 Y代表一直接鍵結，或 R5 R4 其中 R1與R2分別獨立代表氳、氣、溴、氟、環戊胺 -94 -Where Y represents a direct bond, or R5 R4 where R1 and R2 each independently represent arsine, gas, bromine, fluorine, cyclopentylamine -94-

本紙張尺度適用中國國家標準(CNS)A4規格（210x297公釐）經濟部智慧財產局員工消費合作社印製 200404052 f、申請專利範圍基、三氟曱基或三氟甲氧基； R3、R4與R5分別代表氫；且 Z1與Z2分別代表氫。 5.根據申請專利範圍第1項之式(I)羥基-四氫-萘脲衍生物、其互變異構型或立體異構型、或其鹽，其中 X 代表This paper size applies to China National Standard (CNS) A4 (210x297 mm) printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs, 200404052 f, patent application scope, trifluorofluorenyl or trifluoromethoxy; R3, R4 and R5 each represents hydrogen; and Z1 and Z2 each represent hydrogen. 5. A hydroxy-tetrahydro-naphthyl urea derivative of formula (I), its tautomeric or stereoisomeric form, or a salt thereof according to item 1 of the scope of the patent application, where X represents

其中 Y代表一直接鍵結，或 R5 R4 其中 R1與R2分別獨立代表氩、氯、溴、氟、環戊胺基、三氟甲基或三氟甲氧基； R3、R4與R5分別代表氫；且 Z1與Z2分別代表氫。 6.根據申請專利範圍第1項之式(I)羥基-四氫-萘脲衍生物、其互變異構型或立體異構型、或其鹽，其中該式(I) 羥基-四氫-莕脲衍生物係選自下列各物組成之群中： N-[4-氯-3-(三氟甲基）笨基]-N’-(7-羥基-5,6,7,8-四氫冬萘 -95 - 本紙張尺度適用中國國家標準(CNS)A4規格（210x297公釐）Where Y represents a direct bond, or R5 R4 where R1 and R2 each independently represent argon, chlorine, bromine, fluorine, cyclopentylamino, trifluoromethyl or trifluoromethoxy; R3, R4 and R5 represent hydrogen ; And Z1 and Z2 each represent hydrogen. 6. A hydroxy-tetrahydro-naphthyl urea derivative of formula (I), a tautomeric or stereoisomeric form thereof, or a salt thereof according to item 1 of the scope of the patent application, wherein the formula (I) hydroxy-tetrahydro- The fluorenil derivative is selected from the group consisting of: N- [4-chloro-3- (trifluoromethyl) benzyl] -N '-(7-hydroxy-5,6,7,8- Tetrahydronaphthalene-95-This paper size applies to China National Standard (CNS) A4 (210x297 mm)

200404052 經濟部智慧財產局員工消費合作社印製 A8 B8 C8 D8 申請專利範圍基)脲； N-(3-氣苯基)-Ν’-(7-^έ 基-5,6,7,8-四鼠-1-奈基)脈， N-(7-羥基-5,6,7,8-四氫-1-萘基)-N’-[3-(三氟甲基）苯基] 脲； N-(7-羥基-5,6,7,8-四氫-1_萘基)->^[4-(三氟甲基）苯基] 脲； 3-({[(7-故基-5,6,7,8-四氮小審基）胺基]罗炭基}胺基）苯甲酸乙酯； N-(7_羥基-5,6,7,8-四氫-1-萘基萘基)脲； N-(7-^i 基-5,6,7,8_ 四鼠-1-奈基)-N’-(2_ 茶基)脈， N-(3,4_二氯苯基)-N’-(7-羥基-5,6,7,8-四氫小萘基)脲； N-(7-羥基-5,6,7,8-四氫小莕基)-N’-(4-異丙基苯基)脲；基-5,6,7,8-四鼠-1-審基)-N’-(4-苯氧基苯基）脈， N-[4_氯-3-(三氟甲基）苯基]-N’-(7_羥基-5,6,7,8-四氫小萘基)脈， N-(7-羥基-5,6,7,8-四氫-1-萘基)->1’-苯基脲； N-(4-氣苯基)-Nf-(7-羥基-5,6,7,8-四氫小萘基)脲； N-(7-羥基-5,6,7,8-四氫小萘基)-冲-[2-(三氟甲基）苯基] 脲； N-(7-羥基-5,6,7,8-四氫-1-萘基)-N’-[4-(三氟曱基）苯基] 脈， N-(3,4-二氯苯基)-N’-(7-羥基-5,6,7,8-四氫-1_萘基)脲； N-(7-羥基-5,6,7,8-四氫小萘基)-沖-[4-(三氟甲氧基）苯基] 脲； -96 - 本紙張尺度適用中國國家標準(CNS)A4規格（210x297公釐） 200404052 A B c D t、申請專利範圍 N-(7-羥基-5,6,7,8-四氫小萘基)-N’_[4-(三氟甲氧基）苯曱基]脲； N-(7-經基-5,6,7,8 -四氳-1 -萘基)-Ντ-(2,4,6-三甲氧苯甲基)脲； N-(2,6-二氟苯甲基)-Nf-(7-羥基-5,6,7,8-四氫小萘基)脲； N-(7-羥基-5,6,7,8-四氫-1-萘基)-N’-[4-(三氟甲基）苯甲基] 腺， N-(7-羥基-5,6,7,8-四氫-1-萘基)-N’-[4-(三氟甲氧基）苯甲基]脲； N-[2-(4-氯苯基）乙基]-N’-(7-經基-5,6,7,8-四氮-1-茶基）脲；與 N-[3-氟-4-(三氟甲基）苯甲基]-N’-(7-羥基-5,6,7,8-四氫-1- 萘基)脈。 7. —種式(I)羥基-四氫-萘脲衍生物，其中該式(I)羥基-四氫-萘脲衍生物係選自下列各物組成之群中： N-[4-氯-3-(三氟曱基）苯基]-N’-[(7S)-7-羥基-5,6,7,8-四氮-1-茶基]脈，經濟部智慧財產局員工消費合作社印製 N-[4-氯-3-(三氟甲基）苯基]-N’-[(7R)-7-羥基-5,6,7,8-四氫-1-萘基]脲； N-[(7R)-7_羥基-5,6,7,8-四氫小萘基]-N，-[4-(三氟甲基）苯曱基]脲； N-[(7S)-7-羥基-5,6,7,8-四氫小萘基]-N’-[4-(三氟甲基)-苯甲基]脲； -97 - 本紙張尺度適用中國國家標準(CNS)A4規格（210 X297公釐） 200404052 六經濟部智慧財產局員工消費合作社印製 A8 B8 C8 D8 申請專利範圍 N-[(7R)_7-羥基 _5,6,7,8_ 四氫-1-萘基]-N，-[4-(三氟甲氧基)-苯甲基]脲；及 N-[(7S)-7-羥基-5,6,7,8-四氫冬萘基]-N’-[4-(三氟甲氧基)-苯甲基]脲。 8. —種醫藥品，其包含根據申請專利範圍第1項之式(I) 羥基-四氫-萘脲衍生物、其互變異構型或立體異構型、或其生理上可接受之鹽作為活性成分。 9. 根據申請專利範圍第8項之醫藥品，其尚包含一種或多種醫藥上可接受之賦形劑。 10. 根據申請專利範圍第8項之醫藥品，其中該式⑴羥基-四氫-萘脲衍生物、其互變異構型或立體異構型、或其生理上可接受之鹽為VR1擷抗劑。 11. 根據申請專利範圍第8項之醫藥品，其係用於治療與/ 或預防泌尿病變或疾病。 12. 根據申請專利範圍第11項之醫藥品，其中該泌尿病變或疾病為尿急性尿失禁或過度活性膀胱。 13. 根據申請專利範圍第8項之醫藥品，其係用於治療與/ 或預防疼痛。 14. 根據申請專利範圍第13項之醫藥品，其中該疼痛為慢性疼痛、神經病變性疼痛、手術後疼痛或類風濕關節炎疼痛。 15. 根據申請專利範圍第8項之醫藥品，其係用於治療與/ 或預防與疼痛有關之病變或疾病。 16. 根據申請專利範圍第15項之醫樂品’其中該與疼痛有 -98 - 本紙張尺度適用中國國家標準(CNS)A4規格（210x297公釐） 200404052200404052 Intellectual Property Bureau of the Ministry of Economic Affairs prints A8 B8 C8 D8 patent application scope) Urea; N- (3-Gaphenyl) -N '-(7- ^ έ-5,6,7,8- Tetramur-1-naphthyl) vein, N- (7-hydroxy-5,6,7,8-tetrahydro-1-naphthyl) -N '-[3- (trifluoromethyl) phenyl] urea ; N- (7-hydroxy-5,6,7,8-tetrahydro-1-naphthyl)-> ^ [4- (trifluoromethyl) phenyl] urea; 3-({[((7- Ethyl-5,6,7,8-tetraazatriaminyl) amino] carbo} amino) benzoic acid ethyl ester; N- (7_hydroxy-5,6,7,8-tetrahydro- 1-naphthylnaphthyl) urea; N- (7- ^ i group-5,6,7,8_ tetramur-1-enyl) -N '-(2_theanyl) vein, N- (3,4 _Dichlorophenyl) -N '-(7-hydroxy-5,6,7,8-tetrahydrosmallnaphthyl) urea; N- (7-hydroxy-5,6,7,8-tetrahydroberberine ) -N '-(4-isopropylphenyl) urea; pentyl-5,6,7,8-tetramus-1-yl) -N'-(4-phenoxyphenyl) vein, N- [4_chloro-3- (trifluoromethyl) phenyl] -N '-(7_hydroxy-5,6,7,8-tetrahydrosmallnaphthyl) vein, N- (7-hydroxy- 5,6,7,8-tetrahydro-1-naphthyl)-> 1'-phenylurea; N- (4-phenyl) -Nf- (7-hydroxy-5,6,7,8 -Tetrahydro small naphthyl) urea; N- (7-hydroxy-5,6,7,8-tetrahydro small naphthyl) -Chong- [2- (trifluoromethyl) phenyl] Urea; N- (7-hydroxy-5,6,7,8-tetrahydro-1-naphthyl) -N '-[4- (trifluorofluorenyl) phenyl] vein, N- (3,4- Dichlorophenyl) -N '-(7-hydroxy-5,6,7,8-tetrahydro-1-naphthyl) urea; N- (7-hydroxy-5,6,7,8-tetrahydro small Naphthyl) -Chong- [4- (trifluoromethoxy) phenyl] urea; -96-This paper size applies to Chinese National Standard (CNS) A4 (210x297 mm) 200404052 AB c D t, scope of patent application N- (7-hydroxy-5,6,7,8-tetrahydrosmallnaphthyl) -N '_ [4- (trifluoromethoxy) phenylfluorenyl] urea; N- (7-meryl-5 , 6,7,8-tetrafluorene-1 -naphthyl) -Nτ- (2,4,6-trimethoxybenzyl) urea; N- (2,6-difluorobenzyl) -Nf- ( 7-hydroxy-5,6,7,8-tetrahydrosmallnaphthyl) urea; N- (7-hydroxy-5,6,7,8-tetrahydro-1-naphthyl) -N '-[4- (Trifluoromethyl) benzyl] gland, N- (7-hydroxy-5,6,7,8-tetrahydro-1-naphthyl) -N '-[4- (trifluoromethoxy) benzene Methyl] urea; N- [2- (4-chlorophenyl) ethyl] -N '-(7-Cyclo-5,6,7,8-tetraaza-1-theyl) urea; and N -[3-Fluoro-4- (trifluoromethyl) benzyl] -N '-(7-hydroxy-5,6,7,8-tetrahydro-1-naphthyl) vein. 7. —Hydroxy-tetrahydro-naphthyl urea derivative of formula (I), wherein the hydroxy-tetrahydro-naphthyl urea derivative of formula (I) is selected from the group consisting of: N- [4-chloro -3- (trifluorofluorenyl) phenyl] -N '-[(7S) -7-hydroxy-5,6,7,8-tetraaza-1-tea-based] vein, consumed by employees of the Intellectual Property Bureau of the Ministry of Economic Affairs Cooperative printed N- [4-chloro-3- (trifluoromethyl) phenyl] -N '-[(7R) -7-hydroxy-5,6,7,8-tetrahydro-1-naphthyl] Urea; N-[(7R) -7-hydroxy-5,6,7,8-tetrahydrosmallnaphthyl] -N,-[4- (trifluoromethyl) phenylfluorenyl] urea; N-[( 7S) -7-hydroxy-5,6,7,8-tetrahydrosmallnaphthyl] -N '-[4- (trifluoromethyl) -benzyl] urea; -97-This paper is applicable to China Standard (CNS) A4 specification (210 X297 mm) 200404052 Printed by the Consumer Property Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs A8 B8 C8 D8 Patent application scope N-[(7R) _7-hydroxy_5,6,7,8_ -1-naphthyl] -N,-[4- (trifluoromethoxy) -benzyl] urea; and N-[(7S) -7-hydroxy-5,6,7,8-tetrahydrone Naphthyl] -N '-[4- (trifluoromethoxy) -benzyl] urea. 8. A pharmaceutical product comprising a hydroxy-tetrahydro-naphthyl urea derivative of formula (I) according to item 1 of the scope of the patent application, a tautomeric or stereoisomeric form thereof, or a physiologically acceptable salt thereof As an active ingredient. 9. The pharmaceutical product according to item 8 of the scope of patent application, which further comprises one or more pharmaceutically acceptable excipients. 10. The pharmaceutical product according to item 8 of the scope of patent application, wherein the hydroxy-tetrahydro-naphthyl urea derivative of the formula, its tautomeric or stereoisomeric form, or its physiologically acceptable salt is VR1 antibody Agent. 11. The pharmaceutical product according to item 8 of the scope of patent application, which is used for the treatment and / or prevention of urinary diseases or diseases. 12. The pharmaceutical product according to item 11 of the scope of patent application, wherein the urinary disease or disease is urinary acute incontinence or an overactive bladder. 13. The pharmaceutical product according to item 8 of the scope of patent application, which is used for the treatment and / or prevention of pain. 14. The pharmaceutical product according to item 13 of the application, wherein the pain is chronic pain, neuropathic pain, post-operative pain, or rheumatoid arthritis pain. 15. The pharmaceutical product according to item 8 of the scope of patent application, which is used for the treatment and / or prevention of pain-related diseases or diseases. 16. According to the item 15 of the scope of patent application, which is related to pain -98-This paper size is applicable to China National Standard (CNS) A4 (210x297 mm)

六、申請專利範圍受關之病變或疾病為神經痛、神經病變、痛覺、神傷、絕血、神經變性或中風： 17·根據申請專利範圍第8項之醫藥品，其係用於治療與/ 或預防發炎病變或疾病。 18·根據申請專利範圍第17項之醫藥品，其中該發炎病變或疾病為氣喘或COPD。 19·一種以根據申請專利範圍第丨項之化合物於製造醫乘品供冶療與/或預防泌尿病變或疾病上之用途。 20.—種以根據申請專利範圍第丨項之化合物於製造醫藥品供治療與/或預防疼痛上之用途。 21·—種以根據申請專利範圍第丨項之化合物於製造醫藥品供治療與/或預防發炎病變或疾病上之用途。 22·—種控制人類與動物之泌尿病變或疾病之方法，其包括投與VR1-擷抗有效量之至少一種根據申請專利範圍第 1項之化合物。 23·—種控制人類與動物之疼痛之方法，其包括投與VR1_ 擷抗有效量之至少一種根據申請專利範圍第丨項之化合物。經濟部智慧財產局員工消費合作社印製 24·—種控制人類與動物之發炎病變或疾病之方法，其包括投與VR1-擷抗有效量之至少一種根據申請專利範圍第 1項之化合物。 99 - 本纸張尺度適用中國國家標準(CNS)A4規格（210x297公爱） 200404052 (一）、本案指定代表圖為：第__圖（無) (二）、本代表圖之元件代表符號簡單說明·· 益 46. The disease or disease covered by the scope of patent application is neuralgia, neuropathy, pain, distress, hemostasis, neurodegeneration or stroke: 17. Medicines according to item 8 of the scope of patent application, which are used for treatment and / Or prevent inflammatory lesions or diseases. 18. The pharmaceutical product according to item 17 of the scope of patent application, wherein the inflammatory lesion or disease is asthma or COPD. 19. A use of a compound according to the scope of the patent application for the manufacture of medical products for the treatment and / or prevention of urinary diseases or diseases. 20.-Use of a compound according to item 丨 of the scope of patent application for the manufacture of pharmaceuticals for the treatment and / or prevention of pain. 21 · —The use of a compound according to item 丨 of the scope of patent application for the manufacture of pharmaceuticals for the treatment and / or prevention of inflammatory lesions or diseases. 22. A method of controlling urinary pathological changes or diseases in humans and animals, which comprises administering an effective amount of at least one compound according to item 1 of the patent application. 23. A method of controlling pain in humans and animals, which comprises administering an anti-VR1_ effective amount of at least one compound according to the scope of the patent application. Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs 24. A method for controlling inflammatory lesions or diseases of humans and animals, which comprises administering VR1-capable anti-effective amount of at least one compound according to item 1 of the scope of patent application. 99-This paper size is in accordance with the Chinese National Standard (CNS) A4 specification (210x297 public love) 200404052 (1). The designated representative map in this case is: Figure __ (none) (II). The component representative symbol of this representative map is simple. Explanation ...

本案若有化學式時，請揭示最能顯示發明特徵的化學式：〇If there is a chemical formula in this case, please disclose the chemical formula that best shows the features of the invention: 〇

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